Journal of Cardiac Failure Vol. 13 No. 2 2007

Perspective

Myocellular and Interstitial Edema and CirculatingVolume Expansion as a Cause of Morbidity

and Mortality in Heart Failure

ANDREW BOYLE, MD,1 MATHEW S. MAURER, MD,2 AND PAUL A. SOBOTKA, MD3

Minneapolis, Minnesota; New York, New York

ABSTRACT

Background: Total body sodium and volume overload are the hallmarks of the congested state in theheart failure patient and result in a variety of deleterious pathophysiologic outcomes including ventricularchamber dilation, passive congestion of both encapsulated and nonencapsulated vital organs and myocar-dial edema and ischemia.Methods and Results: We propose that congestion is itself a disease state irrespective of the underlyingcardiac or renal dysfunction and that sodium and volume overload are directly related to poor clinical out-comes in such patients. In this model, the target of decongestion therapy should be normalization of totalbody sodium and volume in an expeditious manner and with a durable result.Conclusions: Additionally, novel tools to continuously measure the effectiveness and adequacy of decon-gestion therapy in all compartments are required if improved clinical outcomes are to be attained. (J Car-diac Fail 2007;13:133e136)Key Words: Congestion, Renal dysfunction, Sodium, Ventricular dilation.

We propose that increases in interstitial and intracellularedema and vascular engorgement can mediate both organdysfunction and systemic illness, irrespective of whetherthe congestion arises from a cardiac or renal etiology.This construct has clinical implications, namely that thetreatment of edema and vascular engorgement should targetnormalization of both interstitial sodium and water contentas well as normalization of circulating volume, and that thetreatment of congestion assumes a significant clinical im-portance. The purpose of this perspective is to focus atten-tion on the mechanisms by which both edema and volumeexpansion can alone cause myocellular, ventricular, and

From the 1Division of Cardiology, University of Minnesota, Minnea-polis, Minnesota; 2Division of Cardiology, Columbia University Schoolof Medicine, New York, New York; and 3Division of Cardiology, Hennepin,County Medical Center, Minneapolis, Minnesota.

Manuscript received March 28, 2006; revised manuscript receivedSeptember 6, 2006; revised manuscript accepted October 24, 2006.

Reprint requests: Andrew Boyle, MD, Division of Cardiology, Univer-sity of Minnesota, MMC 508, 420 SE Delaware Street, Minneapolis,MN 55455.

1071-9164/$ - see front matter� 2007 Elsevier Inc. All rights reserved.doi:10.1016/j.cardfail.2006.10.015

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systemic pathology. Recognizing congestion itself as a dis-ease state, rather than purely as a consequence of eitherventricular or renal disorders adds critical emphasis on de-fining appropriate targets for decongestion therapy. Ulti-mately, if normalization of total body sodium and wateris to become the primary objective of decongestive therapy,novel methods to continuously assess volume status andvolume distribution in real time are critical to monitor theeffectiveness and adequacy of the chosen therapy.

It’s the Volume, Not the Serum Creatinine

Sodium is the major determinant of extracellular fluidvolume. The plasma volume is in turn determined by theextracellular fluid volume and the partitioning of this vol-ume between the extra- and intravascular compartments,governed by Starling hydrostatic and oncotic forces. Addi-tionally, the autonomic nervous system, through alterationsin neurohormonal activation that result in salt and water re-tention as well as alterations in venous tone and capaci-tance, particularly in the splanchnic bed, affect theamount and distribution of intravascular volume. Small

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134 Journal of Cardiac Failure Vol. 13 No. 2 March 2007

increases in sodium retention from increased renotubularreabsorption result in significant intravascular volumeexpansion with subsequent rises in transcapillary hydro-static pressure and a resultant transudation of solute intothe interstitial space and eventually, also into the intracellu-lar compartment. The observed increase in intravascular so-dium and volume will also dilute the serum concentrationsof albumin and other proteins thereby reducing intravascu-lar oncotic pressure and promoting further extravasation offluid into the interstitial space. Thus regulation of sodiummetabolism is critical in understanding the mechanismsby which total body volume itself is regulated.

There is no clinically vetted and commonly applied mea-sure of circulating volume or interstitial volume, nor aretheir accepted methods to assess the distribution of circulat-ing volume. Clinicians rely on physical findings, such asjugular venous distension, and laboratory assessments,predominately of renal function, to assess volume status.However, there is a poor correlation between both physicalsigns or patient symptoms of congestion and the degree ofcirculating blood volume expansion.1,2 Serum creatinine,a marker of renal glomerular filtration rate, and serumblood urea nitrogen concentration both give insight into re-nal sodium management only late in the progression ofmost renal diseases. Furthermore, a rise in serum bloodurea nitrogen and creatinine concentrations may also occurif sodium and volume removal proceeds at a rate that ex-ceeds the plasma refill rate from the interstitium and mayprecede complete decongestion of the patient. A mild re-duction in glomerular filtration rates with correspondingrises in serum creatinine are associated with significantmorbidity and mortality in both asymptomatic and symp-tomatic heart failure,3,4 after myocardial infarction,5 and af-ter cardiac surgery.6 However, these markers of glomerularfunction give only partial insight into tubular function,which is the primary site of salt and water metabolism.Enhanced renotubular sodium and water reabsorption, as aresult of activation of neurohormonal axes such as thesympathetic nervous system and the renin-angiotensin-aldosterone system, or as a primary defect in sodium homeo-stasis, leads to total body volume expansion and edema.Thus, although volume expansion almost always accom-panies a reduction in estimated glomerular filtration rateand a rise in serum creatinine, volume expansion may alsooccur purely on the basis of a change in renotubular absorp-tion in the absence of a decline in glomerular filtration rateor an elevation in serum creatinine.

A sodium and volume expanded state can lead to furtherimpairment in renal and cardiac function. Consequently,achieving an appropriate balance of total body sodium,and therefore total body volume, is crucial in establishinga fully decongested state in heart failure and may lead toimproved renal function and clinical outcomes. This modeloffers a rational explanation to account for why a reductionof volume by mechanical sodium and water removal usingultrafiltration has been correlated with altering the clinicalprognosis of volume overloaded heart failure patients and

renal failure patients.7,8 Investigations comparing any inter-vention for reduction of congestion therefore requires thatthe target of therapy, volume, be adequately controlled. Dif-ferent outcomes of experiments comparing congestion ther-apy can be attributed to the inherent differences in thetherapy, or their differential successes in volume reduction.For example, rather than attribute the success of ultrafiltra-tion therapy to something magical being removed in theultrafiltrate, it is entirely possible that the benefits are asso-ciated with attaining dry volumes without adverse clinicalevents.

Interstitial Volume and Circulating Engorgementas Causes of Organ Dysfunction Ventricular

Chamber Dilation and Cardiac Function

Intravascular engorgement secondary to sodium and wa-ter retention may, with time, result in an increase in leftventricular chamber dimensions and is associated witha measurable decline in cardiac performance via numerouspotential mechanisms.9e11 An increase in left ventricularchamber size leads to a corresponding increase in myocar-dial oxygen consumption from increased wall tension ac-cording to LaPlace’s law. This increase in myocardialoxygen requirement may exceed the coronary perfusion ca-pacity resulting in a mismatch between myocardial oxygensupply and demand contributing to a decline in left ventric-ular contractility. Because the inner third of the left ventric-ular myocardium is more at risk for ischemia being moreremote from aortic pressure, increases in left ventricular di-astolic chamber pressure may impair ventricular perfusionsufficiently to cause subendocardial ischemia, if not infarc-tion. The discovery of elevated serum troponin levels incongestive heart failure patients demarks a worse clinicalprognosis.12,13 In the absence of epicardial coronary diseaseto explain myocardial ischemia and necrosis, the hemo-dynamic tamponade of subendocardial blood flow fromincreased interstitial hydrostatic pressure, increasedmyocardial tissue turgor, increased left ventricular end-diastolic pressure, and increased left ventricular myocardialwall tension in the presence of an increased myocardial oxy-gen demand may be potential explanations for congestion-related myocardial necrosis.

Classic physiology may also help to explain the observedcongestion-related reduction of ventricular performance.Impairment of left ventricular filling can be made worsefrom right ventricular distention and pressure overload,which increases pericardial constraint and magnifies the ef-fects of ventricular interdependence. These phenomena areexacerbated in the presence of left ventricular dilation withphysiologic mitral regurgitation that, in turn, can further re-duce effective forward blood flow. Furthermore, the devel-opment of volume-dependent left ventricular asynchronymay also contribute to the impact of vascular engorgementon both left ventricular systolic and diastolic function.14,15

Systemic Effects of Edema

Passive congestion from sodium and water overload ispathogenic for a variety of other encapsulated and nonen-capsulated vital organs, particularly for the kidneys andthe liver. An increase in right atrial pressure directly re-duces glomerular filtration rate at least in part by decreasingthe transrenal perfusion pressure gradient and increasing re-nal capillary hydrostatic pressure.16 Similarly, passive con-gestion of the liver is well known to cause hepatocellularnecrosis and is associated with decreased hepatic syntheticfunction.17 Moreover, passive congestion of the small intes-tine from an elevated right atrial pressure can have a sub-stantial negative effect on absorption of key nutrients aswell as oral medications leading to a profoundly malnour-ished state. The development of bowel edema has alsobeen associated with altered bowel wall permeability tobacterial endotoxin (also known as lipopolysaccharide)with potential translocation into the systemic circulationand eventually enhanced release of inflammatory cytokines,which has been associated with worsened cardiovascularoutcomes.18,19 The combination of decreased gut absorp-tion from bowel edema, decreased hepatic synthesis as aresult of hepatic congestion, and increase serumconcentrations of pro-inflammatory cytokines in end-stageheart failure all lead to a condition known as cardiac ca-chexia, which is associated with a deteriorating clinicalprognosis.20 Fortunately, our generally upright posturespares the brain from venous engorgement of volumeexcess.

Myocardial Interstitial and Cellular Edema

The myocardium is not spared from the harmful effectsof increased total body sodium and water that are observedin both heart failure and renal failure. Movement of fluidbetween vascular, interstitial, and intracellular compart-ments must respond to the same Starling forces, with the in-cremental complexity of periodic increases of intramuralpressures from contraction and passive diastolic distensionof the myocardium. Directly increasing myocardial intersti-tial water content by ligating cardiac veins and obstructingcardiac lymphatic drainage has been demonstrated to resultin extensive myocardial necrosis and infarction as well asreduced left ventricular systolic function.21 A chronic ele-vation of right atrial pressure could achieve a similar com-promise in coronary hemodynamics from a rise in coronaryvenous pressure. The mechanism by which cardiac venousoutflow obstruction causes myocyte necrosis remains to befully elucidated. However, increased myocardial turgorfrom extravasation of fluid into the interstitial space maylead to a decline in myocardial perfusion as well as a declinein delivery of vital myocardial nutrients, including oxygen.With a simultaneously increased myocardial substratedemand from chamber enlargement, further myocardialdysfunction might ensue.

The mechanical consequences of even mild myocardialedema can have profoundly deleterious effects on cardiachemodynamics.22,23 An increase in perfusion pressure inLangendorff hearts caused an increase in global heartweight and was associated with significant reductions inmyocardial contractility and coronary flow rates as wellas reduced ventricular myocardial compliance and worsen-ing diastolic performance.22 Recent hypotheses havesuggested that either circulating excess volume or thedevelopment of cardiac interstitial edema might be theprimary etiologies for ventricular hypertrophy and fibrosisin heart failure with preserved left ventricular systolic func-tion.24 In this case, a reduction in circulating volume andthe resultant reduction in cardiac interstitial sodium andwater might retard the development of left ventricularhypertrophy and fibrosis, or even potentially contributeto the reversal of this syndrome.

Implications

The implications of this construct are multiple. First,experiments comparing different treatment strategies forcongestion must adequately control for their effects oninterstitial and circulating volume. Second, if edema andvolume excess contribute to myocyte ischemia and necro-sis, ventricular hypertrophy, interstitial fibrosis, and physi-ologic ventricular dysfunction including valvular andmechanical derangements, then normalization of volumebecomes a clinical priority. Additionally, experimentsdefining the cellular and systemic pathology of edemabecome critical in defining the potential urgency ofrestoring normal volume. And third, if normalizing intersti-tial fluid and circulating volume are critical therapeutic tar-gets, vetting of diagnostic tools to define these end pointswill be required. Using weight change and clinical mea-sures of jugular venous distension to describe volume andits distribution may prove to be naive. It is further possiblethat appreciation of the salt content of the fluid removedand the impact of different therapies on the volume of dis-tribution of fluid may become important in this model.

References

1. Androne AS, Hryniewicz K, Hudaihed A, Mancini D, Lamanca J,

Katz SD. Relation of unrecognized hypervolemia in chronic heart fail-

ure to clinical status, hemodynamics, and patient outcomes. Am J

Cardiol 2004;93:1254e9.

2. Androne AS, Katz SD, Lund L, Lamanca J, Hudaihed A,

Hryniewicz K, et al. Hemodilution is common in patients with

advanced heart failure. Circulation 2003;107:226e9.

3. Dries DL, Exner DV, Domanski MJ, Greenberg B, Stevenson LW. The

prognostic implications of renal insufficiency in asymptomatic and

symptomatic patients with left ventricular systolic dysfunction. J Am

Coll Cardiol 2000;35:681e9.

4. Schrier RW. Role of diminished renal function in cardiovascular mor-

tality: marker or pathogenetic factor? J Am Coll Cardiol 2006;47:1e8.

5. Anavekar NS, McMurray JJV, Valzquez EJ, Solomon LK, Rouleau JL,

White HD, et al. Relation between renal dysfunction and

Myocellular and Interstitial Edema � Boyle et al 135

136 Journal of Cardiac Failure Vol. 13 No. 2 March 2007

cardiovascular outcomes after myocardial infarction. N Engl J Med

2004;351:1285e95.

6. Lassnigg A, Schmidlin D, Mouhieddine M, Bachmann LM, Druml W,

Bauer P, et al. Minimal changes of serum creatinine predict prognosis

in patients after cardiothoracic surgery: a prospective cohort study.

J Am Soc Nephrol 2004;15:1597e605.

7. Bart BA, Boyle A, Bank AJ, Anand I, Olivari MT, Kraemer M, et al.

Ultrafiltration versus usual care for hospitalized patients with heart

failure: the relief for acutely fluid-overloaded patients with decompen-

sated congestive heart failure (RAPID-CHF) trial. J Am Coll Cardiol

2005;46:2043e6.

8. Costanzo MR, Saltzberg M, O’Sullivan J, Sobotka P. Early ultrafiltra-

tion in patients with decompensated heart failure and diuretic resis-

tance. J Am Coll Cardiol 2005;46:2047e51.

9. Mann DL, Bristow MR. Mechanisms and models in heart failure: the

biomechanical model and beyond. Circulation 2005;111:2837e49.

10. Force T, Michael A, Kelter H, Haq S. Stretch-activated pathways and

left ventricular remodeling. J Card Fail 2002;8(6 Suppl):S351e8.

11. Opie LH, Commerford PJ, Gersch BJ, Pfeffer MA. Controversies in

ventricular remodeling. Lancet 2006;367:356e67.

12. Sugiura T, Takase H, Toriyama T, Goto T, Ueda R, Dohi Y. Circulating

levels of myocardial proteins predict future deterioration of congestive

heart failure. J Card Fail 2005;11:504e9.

13. Rodriguez-Reyna TS, Arrieta O, Castillo-Martinez L, Orea-Tejeda A,

Guevara P, Rebollar V, Granados J. Tumour necrosis factor a and tro-

ponin T as predictors of poor prognosis in patients with stable heart

failure. Clin Invest Med 2005;28:23e9.

14. Yu CM, Zhang Q, Sanderson JE. High prevalence of left ventricular

systolic and diastolic asynchrony in patients with congestive heart fail-

ure and normal QRS duration. Heart 2003;89:54e60.

15. Bader H, Garrigue S, Lafitte S, Reuter S, Jais P, Haissaguerre M, et al.

Intra-left ventricular electromechanical asynchrony: a new indepen-

dent predictor of severe cardiac events in heart failure patients. J

Am Coll Cardiol 2004;43:248e56.

16. Firth JD, Raine AE, Ledingham JG. Raised venous pressure: a direct

cause of renal sodium retention in oedema. Lancet 1988;1:1033e

55.

17. Giallourakis CC, Rosenburg PM, Friedman LS. The liver in heart

failure. Clin Liver Dis 2002;6:947e67.

18. Niebauer J, Wolk HD, Kemp M, Dominguez M, Schumann RR,

Rauchhaus M, et al. Endotoxin and immune activation in chronic heart

failure: a prospective cohort study. Lancet 1999;353:1838e42.

19. Rauchhaus M, Koloczek V, Volk HD, Kemp M, Niebauer J,

Francis DP, et al. Inflammatory cytokines and the possible immuno-

logical role for lipoproteins in chronic heart failure. Intern J Cardiol

2000;76:125e33.

20. Anker SD, Coats AJS. Cardiac cachexia: a syndrome with impaired

survival and immune and neuroendocrine activation. Chest 1999;

115:836e47.

21. Pick R, Miller AJ, Glick G. Myocardial pathology after cardiac venous

and lymph flow obstruction in the dog. Am Heart J 1974;87:627e32.

22. Rubboli A, Sobotka PA, Euler DE. Effect of acute edema on left

ventricular function and coronary vascular resistance in the isolated

rat heart. Am J Physiol 1994;267:H1054e61.

23. Miyamoto M, McClure DE, Schertel ER, Andrew PJ, Jones GA,

Pratt JW, et al. Effects of hypoproteinemia-induced myocardial edema

on left ventricular function. Am J Physiol 1998;247:H937e44.

24. Davis KL, Laine GA, Geissler HJ, Mehlhorn U, Brennan M, Allen SJ.

Effects of myocardial edema on the development of myocardial

interstitial fibrosis. Microcirculation 2000;7:269e80.