Hintze Heart Failure Concepts 99

COMMON MISCONCEPTIONS THAT ARISE IN THE

FIRST-YEAR MEDICAL PHYSIOLOGY CURRICULUM

CONCERNING HEART FAILURE

Thomas H. Hintze and Gong Zhao

Department of Physiology, New York Medical College, Valhalla, New York 10595

There are a number of misconceptions that first-year medical students have

concerning the pathophysiology of heart failure. These stem from 1) a poor

definition of heart failure, 2) a lack of care in distinguishing between similar but

distinct concepts, and 3) the inability to recognize the relationship between the various

stages of heart failure and the clinical manifestation of the disease. In this paper we

provide a list of some of the misconceptions that we have encountered, some

explanations of the distinctions to be made, and some of the rationale behind current

surgical procedures and drug treatment. The misconceptions include failing to differenti-

ate between the Frank-Starling mechanism and cardiac dilation as well as not grasping the

significance that changes in cardiac b-receptor function have in limiting the positive

inotropic actions of circulating catecholamines. Finally, we review some of the altered

neurohumoral mechanisms in heart failure and explain the basis for some common

therapeutic approaches, including the use of angiotensin-converting enzyme inhibitors,

in this disease.

AM. J. PHYSIOL. 277 (ADV. PHYSIOL. EDUC. 22): S260–S267, 1999.

Key words: myocardial failure; circulatory failure; cardiac dilation; cardiac decompensation;

neurohumoral mechanisms in heart failure; peripheral edema

Over the past several years, we have encounteredseveral misconceptions commonly voiced by ourfirst-year medical students regarding the altered hemo-dynamics and clinical manifestations of heart failure.This article reviews many of the underlying conceptsby stating the misconception and then addressing theproblem. First, some background meant to avert someof the problems is given.

The term ‘‘failure’’ is often loosely used in medicineand can refer to any number of clinical entities. Asdefined by Braunwald (2), heart failure is quite simplya ‘‘pathophysiologic state in which an abnormality incardiac function is responsible for the failure of theheart to pump blood at a rate commensurate with theperipheral needs.’’ This can be subdivided into myocar-

dial failure and heart failure. Myocardial failure is somedefect of myocardial contraction, usually in the myo-cyte, which leads to a deficit in overall pump function.The most common example of this is myocyte death,which follows myocardial infarction. In this case, theloss of myocyte mass is responsible for the alteredpump function. Heart failure, on the other hand, canoccur even when myocyte function is normal and canbe defined as the failure of the heart as an organ topump enough blood to support a full range of activity.The best examples of this are acute valve lesions(incompetence or stenosis), where the only defect isin the function of the valve, before remodeling canaffect myocyte function. Another good example ofdeficient cardiac function despite normal myocytecapability is the various forms of pericardial disease. In

A P S R E F R E S H E R C O U R S E R E P O R T

1043 - 4046 / 99 – $5.00 – COPYRIGHT r 1999 THE AMERICAN PHYSIOLOGICAL SOCIETY

VOLUME 22 : NUMBER 1 – ADVANCES IN PHYSIOLOGY EDUCATION – DECEMBER 1999

S260

on April 27, 2011

advan.physiology.orgD

ownloaded from

http://advan.physiology.org/

these cases, whether it be tamponade, fibrosis, oreffusion, the major change is not in the myocyte butrather the impaired filling of the cardiac chambers.When excess fluid is removed from the pericardialspace, arterial pressure returns to normal almostinstantaneously, as most of the students will recognizefrom evening television medical dramas.

Myocyte and cardiac failure should be contrasted withanother type of failure—circulatory failure—in whichsome defect in the circulation leads to reducedperfusion. An example of this is hemorrhage. In thisstate, the myocyte and the valves function normally,yet cardiac output is insufficient to meet peripheraldemands because of reduced blood volume. Obvi-ously, the way to correct this is to replace the lostblood volume.

Another misconception is that all forms of heartfailure are ‘‘congestive.’’ Heart failure often occurswithout congestion, unless the underlying defect islarge and/or long lasting. Congestion is defined as theabnormal accumulation of fluid in the periphery asedema or, in the lung, most evident as rales. Themechanism leading to edema is altered Starling forcesacross the capillary bed, resulting in a net efflux offluid into the tissue.

MISCONCEPTIONS CONCERNING THECONSEQUENCES OF HEART FAILURE

The clinical manifestations of heart failure include lowarterial pressure, tachycardia, exercise intolerance,difficulty breathing (dyspnea) in the supine position,swelling in the extremities, and cachexia. All of theseare manifestations of altered physiological controlmechanisms and the inability of various compensatorymechanisms to restore some level of normal function.

Low arterial pressure and tachycardia are manifesta-tions of the low cardiac output. With the use of theequation mean arterial blood pressure 5 cardiacoutput 3 total peripheral resistance, it is immediatelyobvious that a reduction in cardiac output with othervariables constant results in lower arterial pressure.The accompanying tachycardia is, in part, a barorecep-tor reflex-mediated attempt to increase cardiac out-put. The tachycardia of the failing heart may also becaused by atrial stretch, eliciting a Bainbridge reflex.

The Bainbridge reflex is caused by vagal withdrawal,resulting in only a moderate tachycardia, similar to thetachycardia of heart failure. A common misconceptionthat occurs at this point is that the tachycardia of heartfailure is sympathetic in origin (2). Mild tachycardias,up to heart rates of ,120 beats/min in humans arecaused by the withdrawal of vagal tone and not byrecruitment of sympathetic activity. This misconcep-tion results from the fact that students may have heardthat there is a rise in circulating catecholamines withheart failure, and some well-informed students mayeven know that the best predictor of mortality in heartfailure is the extent to which plasma norepinephrineincreases. At this point, it is helpful to discuss themechanism leading to tachycardia by using the trans-planted human heart as an example. The transplanted(denervated) human heart beats at ,110–120 beats/min, but the denervated heart has no vagal and nosympathetic tone. Because heart rate at rest in aninnervated heart is ,70 beats/min, some mechanismmust lower heart rate from the intrinsic 110 beats/min(seen in the denervated heart) to 70 beats/min in theintact heart. This mechanism is, of course, tonicparasympathetic drive to the sinoatrial (SA) node.Sympathetic drive to the SA node is evident if heartrate is .110 or 120 beats/min, and this only occurslate in the heart failure process.

Heart failure is most obvious in patients with severeexercise intolerance who are gasping for breath andare being treated with digitalis and diuretics. This isreally the end stage of the process, and early interven-tion and diagnosis may better help the patient. Themisconception to be addressed is that all patients withheart failure are bedridden and not able to walkupstairs. This is a good place to bring up the conceptthat heart failure is a dynamic process that is suscep-tible to early diagnosis and treatment. The best way ofillustrating a reduced ability to exercise is to have thepatient with moderate (not severely decompensated)heart failure undergo a stress test and then useGuyton’s curves as shown in Fig. 1. Because of thereduced permissive level of the heart, cardiac outputis reduced during strenuous exercise. Thus, becausethe initial definition of heart failure is a dynamic one,that is, the inability of the heart to perfuse theperiphery, there will be a demonstrable decrease inmaximum cardiac output and, hence, in exercise



S261

on April 27, 2011


ownloaded from


capacity. Patients in the early stages of heart failure,like the patient in Fig. 1, will be able to performmoderate levels of exercise. It is their maximumcapacity that is first affected. This example serves twofunctions, to reinforce the concept of a dynamicdefinition of heart failure and to illustrate the use of a‘‘treadmill stress test,’’ which the students have allheard about. Finally, this allows for a discussion ofGuyton’s concept of the permissive heart, i.e., that theheart will just pump out all of the blood that isreturned to it by the circulation (4).

Another concept that is often misinterpreted by stu-dents is that the extended jugular vein, the prominentjugular venous pressure pulse, the difficulty breathingin the supine position, and the swollen feet thateveryone associates with heart failure are directlyrelated to the reduced output of the heart. Themisconception to be addressed is that the reducedoutput is directly responsible for the accumulation of

fluid in the interstitial space. In fact, it is the rise invenous and capillary pressures that accompany pumpfailure, rather than reduced arterial pressures, thatcauses these various clinical symptoms.

As the ability of the heart to pump blood falls,end-diastolic ventricular pressure will increase be-cause of the reduced ejection. This end-diastolicventricular pressure is transmitted in a retrograde(backward) manner to the atria (increased atrial pres-sure) and further back to the venous and capillarybeds. With the increase in capillary pressure, a netfiltration pressure develops along the entire capillaryand increases movement of fluid into the interstitialspace (Fig. 2) (5). If the right heart is failing, thenpressure at the venous end of peripheral capillarieswill increase, resulting in peripheral edema (swellingin the feet). The retrograde transmission of pressurefrom the right ventricle is also responsible for theobvious jugular venous pressure pulse in patients withheart failure. If the left ventricle is failing, the in-creased filtration occurs in the lungs, resulting ininterstitial edema and the classic rales during ausculta-tion. In addition, because the diffusion of oxygen isinversely proportional to the square of the diffusiondistance, pulmonary interstitial edema can have markedeffects on the movement of oxygen from the alveoli tothe pulmonary capillary blood. This may result inreduced oxygen being carried by the blood, often

FIG. 1.Changes in cardiac output that occur during exercisein normal subjects and in patients with moderateheart failure (HF). Although patients with heart failurecan exercise, the maximum exercise level (i.e., maxi-mum cardiac output) is reduced. This is the basis ofexercise stress testing in patients. Please note that theplateau is flat in compensated heart failure; a descend-ing limb only appears in a decompensated heart.

FIG. 2.Mechanism for increased interstitial fluid accumula-tion during heart failure. A and V, arteriolar andvenular ends of capillary, respectively. Horizontal lineat 25 mmHg is plasma oncotic pressure. In normalstate (dashed line) fluid that is filtered in the first halfof the capillary (filled triangular zone) is reabsorbedin the second half (open triangular zone). Whenvenous pressure rises (solid line), there is filtrationalong more, or most, of the capillary.



S262

on April 27, 2011


ownloaded from


exhibited as blue coloring under the fingernails. All ofthese are examples of backward failure, that is,dysfunction being transmitted in a direction oppositeto the flow of blood.

Another way edema can be generated in the lung andperiphery is as the result of a marked increase in bloodvolume. Renal failure, the inability of the kidney toexcrete a normal urine volume, is often associatedwith heart failure and can be attributed among otherreasons to reduced renal perfusion. This results in anaccumulation of fluid (80% of which is stored in thevenous circulation), an increase in capillary venouspressure, and net movement of fluid into the intersti-tial space. The reduced perfusion pressure (forwardfailure) also affects the liver, resulting in accumulationof potentially toxic metabolites, which circulate to‘‘poison’’ the heart and peripheral organs, furthercontributing to heart failure. Treatment is through theuse of diuretics, which lead to a reduction in venouspressures and reabsorption of the accumulated intersti-tial fluid.

The final misconception related to the clinical signs ofheart failure is that the reduced muscle mass, ca-chexia, in itself is caused by the heart failure and maybe a compensatory mechanism to supply substrate foroxidation in a failing heart. Rather, the cachexia iscaused by cytokines, particularly tumor necrosis fac-tor-a (TNF-a), originally called cachexin (1). TNF-aitself or a combination of cytokines is responsible forthe protein wasting in the periphery and is evidenceof activation of an inflammatory process

MISCONCEPTIONS RELATED TO THECOMPENSATORY PHYSIOLOGICALMECHANISMS THAT OCCURIN HEART FAILURE

Although the cause of heart failure may be eithermyocardial or cardiac in origin, once a decrease infunction occurs a number of physiological mecha-nisms are called into play to compensate for thedefect. If the defect is small or the progression of thedisease slow, these compensatory mechanisms maybe sufficient to restore function to normal, especiallyin the absence of a stress such as exercise. It should bepointed out that the compensatory mechanisms arenot sufficient to restore a normal level of maximumexercise performance. This reinforces the utility of

exercise testing in the early diagnosis of heart failure.Furthermore, these compensatory mechanisms in thelong run are insufficient to maintain cardiac function.Ultimately, along with the evolution of the diseaseprocess itself, they contribute to the progression ofheart failure. These compensatory processes include1) increased secretion of catecholamines from sympa-thetic nerve endings in the heart, the periphery, andthe adrenal glands; 2) recruitment of the Frank-Starling mechanism; and 3) myocardial hypertrophy.

The best way to present these concepts is to remindstudents that they occur in a time-dependent fashion;i.e., secretion of norepinephrine caused by baroreflexunloading (a rapid process), then recruitment of theFrank-Starling mechanism as intravascular volume in-creases (an intermediate process), and finally hypertro-phy that involves protein synthesis (the slowest pro-cess). There are a number of misconceptions relatedto each of these three processes.

The misconceptions associated with the role of in-creased sympathetic tone during the development ofheart failure are many. First, the tachycardia of heartfailure is almost entirely caused by vagal withdrawal(2), as pointed out earlier. Second, there are markedalterations in b-adrenergic receptor affinity, number,and turnover, all of which serve to desensitize theb-adrenergic response. This implies that the sympa-thetic nervous system is unable to regulate inotropicstate in the failing heart. In support of this concept isthe recent therapeutic use of b-adrenergic receptorblocking agents in the treatment of heart failure. Therationale is to block a portion of the receptors,thereby allowing the remaining receptors to upregu-late so that, when stimulated, they will transduce apositive inotropic effect. In addition to receptor desen-sitization, cardiac tissue cathecholamines fall to unde-tectable levels after the development of heart failure(7). This should be taken as evidence of depletion ofnorepinephrine from nerve terminals, however, ratherthan the disappearance of sympathetic nerve endings.

Another misconception is that circulating catechol-amines have an important regulatory function in thefailing heart. In humans, circulating catecholaminelevels ,1,000 pg/ml primarily control substrate use;considerably higher levels are necessary to causeperipheral vasoconstriction or to increase cardiac



S263

on April 27, 2011


ownloaded from


contractility (8). It should be remembered in thiscontext that circulating norepinephrine comes primar-ily from peripheral adrenergic nerve endings and thatthe increase during the development of heart failuremay reflect increased peripheral sympathetic nerveactivity and neurally mediated increases in peripheralresistance. Be that as it may, it should be stressed thatthe best predictor of mortality in patients is the rise incirculating plasma catecholamines.

With regard to the Frank-Starling mechanisms, stu-dents often become confused on two points: 1) thepresense (or absence) of a descending limb on thecardiac function curve and 2) the distinction betweenincreased preload as a compensatory mechanism andcardiac dilation. The increase in cardiac function thatresults from an increase in preload is caused bystretching of existing sarcomeres to cause a moreoptimal overlap and closer apposition of actin andmyosin filaments and increased Ca21 sensitivity [seeaccompanying article in this issue by Solaro (6)]. Itshould be pointed out that, even in Guyton’s diagramsof mild heart failure, there is no descending limb on acardiac output curve (Fig. 1). The plateau of thecardiac output curve is depressed but remains parallelto the x-axis. Only after the development of severeheart failure did Guyton find a true descending limb(Fig. 3). In fact, Guyton suggests that the presence of adescending limb is indicative of a late-stage failingheart. The old idea, now discredited, that cardiacmuscle normally shows a descending limb on aStarling curve arose from studies of isolated hearts thatmay, in fact, have been failing.

A good deal of confusion arises over the differencebetween preload and cardiac dilation. Cardiac dilationis an example of cardiac remodeling and is bestappreciated as a shift in the passive length-tensiondiagram (ventricular compliance curve) as shown inFig. 4. A movement from point A to point B is anincrease in preload and would serve to increasesystolic function. On the other hand, a shift frompoint A to point C is clearly caused by some processthat has made the end-diastolic volume much largerand may not be associated with increased systolicfunction. Initially, if the cardiac dilation is great, theLaPlace formula (T 5 Pr, where T is wall tension, P ispressure, and r is radius) predicts that the wall tensionneeded to overcome the large ventricular volume maybe so great as to result in even greater dysfunction(Fig. 5). Almost all forms of heart failure ultimatelylead to a dilated heart, increased diastolic wall stress,and reduced function. The deleterious effects of toomuch cardiac dilation are the rationale behind theBattista procedure. During that surgery, a large por-tion of the left ventricle is removed, resulting in areduced ventricular diameter, reduced wall stress,increased function, and at least some short-term relieffrom the heart failure. Unfortunately, it is still a matterof some debate as to the long-term outcome of thisprocedure.

FIG. 3.Appearance of a descending limb on a Guyton curve. Adescending limb is indicative of decompensated heartfailure. Up until point D there is a plateau on thecardiac output curve. [Reprinted from Guyton (4).]

FIG. 4.Difference in use of preload and cardiac dilation.Movement from point A to point B does not involverestructuring of the heart, whereas movement frompoint A to point C is caused by restructuring. LV, leftventricular.



S264

on April 27, 2011


ownloaded from


The major misconception concerning cardiac hypertro-phy is that it is ultimately good. Cardiac hypertrophyis the slowest of the compensatory physiologicalmechanisms recruited during the development ofheart failure because it involves a number of pro-cesses, including synthesis of new proteins and remod-eling of the ventricles. Hypertrophy was originallydefined as an increase in weight of the ventricle inhumans on autopsy and was associated with heartfailure. Hypertrophy has also been associated with anincrease in cardiac weight and larger skeletal musclemass after exercise training. In fact, the hypertrophyof heart failure still results in a reduced contractilestate at any level of preload when normalized for mass(Fig. 6). Even with substantial increases in the amountof muscle, the hypertrophied sick heart cannot createa normal level of cardiac output during exercise. Thuseach unit of muscle is still in a negative inotropic state.In contrast, skeletal and cardiac muscle after chronicexercise conditioning are capable of greater levels ofperformance. This has led to the hypothesis that‘‘hypertrophy is not hypertrophy is not hypertrophy’’and also to the important question as to what differ-ences in transcriptional regulation direct the synthesisof new protein during the hypertrophy of exercisecompared with the hypertrophy in a failing heart.

Hypertrophy can be either eccentric or concentric,and it has already been discussed that a large dilated

heart (eccentric hypertrophy) may not be able toovercome the increased wall stress caused by en-larged diastolic diameter. The limitation on concentrichypertrophy as a compensatory mechanism, in whichmyocytes increase in diameter and not length, is thatconcentric hypertrophy of individual myocytes in-creases the diffusion distance for oxygen from thenearest capillary. The maximum predicted diffusiondistance in the heart is ,22–25 µm. When cardiaccells hypertrophy beyond this diameter, the center ofthe myocyte becomes hypoxic and the contractilefunction of that myocyte decreases. Thus, even thoughthe increase in cardiac mass during hypertrophy maycompensate to some degree for the reduced contrac-tile state of each myocyte, ultimately the restructuringof the heart limits both eccentric and concentrichypertrophy as adaptive mechanisms, and these mayactually contribute to cardiac dysfunction (Fig. 5).

MISCONCEPTIONS CONCERNING THEINTEGRATED NEUROHUMORAL CONTROL OFTHE CIRCULATION DURING THEDEVELOPMENT OF HEART FAILURE

Perhaps the most useful diagram to explain theintegrated neurohumoral control of the circulationduring the development of heart failure is the onedevised by Guyton (4) (Fig. 7) and modified by us.

FIG. 5.Scheme illustrates concept that alterations in structure of the heart serve tonormalize stress (sm). Eccentric hypertrophy may initially increase functionbut later results in a marked increase in diastolic wall stress. On the other hand,concentric hypertrophy initially results in reduced systolic stress. All forms ofheart failure are eventually characterized by cardiac dilation. [Reprinted fromGrossman (3).]



S265

on April 27, 2011


ownloaded from


Students use this diagram to explain to themselveshow blood volume is increased as heart failure devel-ops. A common misconception that students make atthis point, however, is that the increase in bloodvolume that occurs during heart failure is bad; i.e., itexacerbates the reduction in cardiac output. How-ever, if blood volume is not allowed to expandinitially, and perhaps as far as the intermediate stage ofheart failure, cardiac pump function will be reducedbecause of an inability to recruit the Frank-Starlingmechanism. Moreover, the driving force for eccentrichypertrophy, an increase in end-diastolic wall stress(3), will be lost. This may result in premature mortal-ity. Students may falsely reason that an increase inblood volume moves the heart onto the descendinglimb of the Frank-Starling curve, resulting in a furtherreduction in cardiac function. For that to occur, themechanical function of the heart must have alreadydeteriorated to the point of severe failure (Fig. 3). Inthe early stages of failure, however, function is de-scribed by a normal cardiac output relationship with aplateau (albeit reduced) rather than a descending limb(Fig. 1). Thus the major consequence of increased

blood volume early in the disease is not a reducedcardiac output but rather an increased venous pres-sure (Fig. 2), resulting in pulmonary and systemicedema (backward failure). These are important consid-erations for the medical student because they providethe rational basis for treating heart failure. Treatmentis aimed at correcting defects in inotropic state andvolume regulation.

The updated version of the original diagram devisedby Guyton (Fig. 7) includes drugs that the first-yearmedical student has undoubtedly heard about, includ-ing angiotensin-converting enzyme inhibitors, aldoste-rone blocking agents, and angiotensin II receptorblocking agents, along with the original drugs dis-cussed by Guyton, which included digitalis and diuret-ics. All of these agents contribute to the pharmacologi-cal management of the increased blood volume thatoccurs as a normal compensatory mechanism (and isgood) during the development of heart failure. Further-more, the critical and time-dependent use of theseagents to prevent real volume overload (which is bad)in a decompensated heart may prolong survival. One

FIG. 6.Effects of hypertrophy and heart failure on inotropic state. Note thatwhen normalized for muscle mass, the hypertrophied papillary muscle isstill in a negative inotropic state. RVH, right ventricular hypertrophy;CHF, congestive heart failure; Lmax, maximum length. [Reprinted fromSpann et al. (7).]



S266

on April 27, 2011


ownloaded from


has to be cautious to prevent the misconception thatheart failure is curable. It is not, and heart failurewill still be an epidemic cause of death in the 21stcentury.

In summary, in this review we have tried to addresssome misconceptions often encountered in discus-sions with first-year medical students. Examples aregiven using some recent clinical protocols such as theBattista operation and some newer types of drugsused in the treatment of heart failure. Finally, theconcept of decompensated heart failure and theconcept of a dynamic definition of heart failure havebeen reiterated to support the notion that decompen-sated heart failure is the end result of the diseaseprocess.

Address for reprint requests and other correspondence: T. H.Hintze, Dept. of Physiology, New York Medical College, Valhalla,NY 10595 (E-mail: [email protected]).

References

1. Beutler, B., and A. Cerami. The biology of cachexin/TNF, aprimary mediator of the host response. Annu. Rev. Immunol. 7:625–655, 1989.

2. Braunwald, E. Heart Disease: A Textbook of CardiovascularMedicine. Philadelphia, PA: Saunders, 1980.

3. Grossman, W., D. Jones, and L. P. McLaurin. Wall stress andpatterns of hypertrophy in the human left ventricle. J. Clin.Invest. 56: 56–64, 1975.

4. Guyton, A. C. Textbook of Medical Physiology. Philadelphia,PA: Saunders, 1986.

5. Selkurt, E. E. Physiology. Boston, MA: Little, Brown, 1971.6. Solaro, R. J. Integration of myofilament response to Ca21 with

cardiac pump regulation and pump dynamics. Am. J. Physiol.277 (Adv. Physiol. Educ. 22): S155–S163, 1999.

7. Spann, J. F., Jr., R. A. Buccino, E. H. Sonnenblick, and E.Braunwald. Contractile state of cardiac muscle obtained fromcats with experimentally produced ventricular hypertrophy andheart failure. Circ. Res. 21: 341–349, 1967.

8. Young, M. A., T. H. Hintze, and S. F. Vatner. Correlationbetween cardiac performance and plasma catecholamines in theconscious dog. Am. J. Physiol. 249 (Heart Circ. Physiol. 18):H49–H56, 1985.

FIG. 7.Neurohumoral mechanisms during heart failure. The decrease in pumpfunction results in neurohumoral activation and salt and water retention.Standard treatment has included inotropic agents, such as digitalis, anddiuretics. Newer approaches include an angiotensin-converting enzymeinhibitor (ACE I) or an aldosterone antagonist (Aldo). Nitroglycerin iseffective because it dilates veins (by releasing nitric oxide) and reducescardiac filling pressure. The goal of all these treatments is to adjust fillingpressure to some optimum value to maintain cardiac function. ADH,antidiuretic hormone. [Modified from Guyton (4).]



S267

on April 27, 2011


ownloaded from


Documents

Hintze Heart Failure Concepts 99