Although the designation “heart failure” is routinely used to describe a clinical syndrome recognized by physicians, the exact definition of that syndrome has proved difficult, if not impossible (Table 1-1).1,2 Traditionally, the expression heart failure has been used by physicians to refer to a clinical syndrome that is a constellation of symptoms and signs, usually (but not exclusively) caused by an abnormality of the heart. Note that this traditional usage describes a symptomatic state.

Almost any abnormality of the heart can cause the syndrome of heart failure.3 Rhythm and conduction disturbances, valvular stenosis and incompetence, pericardial and epicardial abnormalities, inherited (congenital) defects, and ventricular dysfunction can each cause heart failure. Ventricular dysfunction has been the focus of most pathophysiological and therapeutic research. It can arise from abnormalities of the myocyte, extracellular matrix, or, usually, both. Myocyte loss (due to infarction, infection, or toxic necrosis) and replacement by scar tissue leads to a reduction in contractility and ejection of blood from the ventricle, that is, predominant systolic dysfunction. Conversely, myocyte hypertrophy and associated extracellular matrix overgrowth (fibrosis) may lead to impaired ventricular filling, that is, predominant diastolic dysfunction. Rarer causes of ventricular dysfunction include disorders causing deposition of abnormal proteins within the ventricular tissue, for example, amyloid.

These diverse etiologies lead to a clinical syndrome, which, by definition, has many common features, notably dyspnea, fatigue, and sodium and water retention (“congestion”).4 Different causes may, of course, also have distinguishing features, for example, a murmur in valve disease and a bradycardia in patients with a conduction disturbance.


Central to the problem of defining and recognizing the syndrome of heart failure is the non-specificity of its cardinal clinical manifestations.5 While that problem can be solved by appropriate investigation, the greater question is what causes those characteristic manifestations in the first place?


Previously popular and simple notions that heart failure can be equated to some measurement of cardiac function, for example cardiac output, can be quickly dispelled.1,2 Measurements such as cardiac output may be normal (especially at rest) and patients with abnormal cardiac function (e.g., a low left ventricular ejection fraction) may be asymptomatic. Of course, patients with heart failure, unless it is advanced, are usually only symptomatic on exertion. Consequently, a widely accepted concept of heart failure is one in which the fundamental problem is inadequate delivery of blood to meet the needs of the metabolizing tissues.1,2 Two qualifications usefully refine this construct. One is to state that this abnormal state exists despite an adequate left ventricular filling pressure.1,2 The second identifies the problem as one of inadequate oxygen delivery rather than inadequate


HEART FAILURE: A PRACTICAL APPROACH TO TREATMENT


Table 1-1 Definitions of heart failure

1933 A condition in which the heart fails to discharge its contents adequately. (Lewis.)

1950 A state in which the heart fails to maintain an adequate circulation for the needs of the body

despite a satisfactory filling pressure. (Wood.)

1980 A pathophysiological state in which an abnormality of cardiac function is responsible for the

failure of the heart to pump blood at a rate commensurate with the requirements of the

metabolizing tissues. (Braunwald.)

1985 A clinical syndrome caused by an abnormality of the heart and recognized by a characteristic

pattern of hemodynamic, renal, neural, and hormonal responses. (Poole-Wilson.)

1987 syndrome...Which arises when the heart is chronically unable to maintain an appropriately high

blood pressure without support. (Harris.)

1988 A syndrome in which cardiac dysfunction is associated with reduced exercise tolerance, a high

incidence of ventricular arrhythmias, and shortened life expectancy. (Cohn.)

1989 ...ventricular dysfunction with symptoms.... (Anonymous.)

1993 Heart failure is the state of any heart disease in which, despite adequate ventricular filling, the

heart’s output is decreased or in which the heart is unable to pump blood at a rate adequate

for satisfying the requirements of the tissues with function parameters remaining within

normal limits. (Denolin et al.)

1994 The principal functions of the heart are to accept blood from the venous system, deliver it to

the lungs where it is oxygenated (aerated), and pump the oxygenated blood to all body

tissues. Heart failure occurs when these functions are disturbed substantially. (Lenfant.)

1996 Abnormal ventricular function, symptoms or signs of heart failure (past or current), and on

treatment (with a favorable response to treatment). (Poole-Wilson.)

2005 (i) Symptoms of heart failure (at rest or during exercise) and (ii) objective evidence (preferably

by echocardiography) of cardiac dysfunction (systolic and/or diastolic) at rest (both criteria [i]

and [ii] must be fulfilled) and (iii) in cases where the diagnosis is in doubt, response to

treatment directed towards heart failure.


Source: Adapted from Purcell IF, Poole-Wilson PA. Heart failure: why and how to define it? Eur J Heart Fail. 1999;1:7–10.


blood flow.1,2 The importance of both these qualifications is clear. Obviously, blood flow and oxygen delivery will be inadequate, despite good pump function, when there is intravascular volume depletion and reduced oxygen carrying capacity, for example, as a result of severe hemorrhage. The paradigm of inadequate oxygen delivery despite normal filling pressure also has merit in that it allows for “high-output” syndromes of heart failure such as seen in patients with anemia, thyrotoxicosis, Paget’s disease, arteriovenous shunting, and so on. It is still, however, a physiological rather than clinical definition, and measurement of inadequate delivery of oxygen to the metabolizing tissues is not easily done. More fundamentally, this construct does not explain how inadequate oxygen delivery (if indeed that is the primary problem) is sensed by the body and how the body responds to it. It is likely that it is the responses of the body that lead to the clinical syndrome recognized by clinicians. These responses are almost certainly multiple, complex, and variable. However, one thing is certain and that is the pivotal role played by the kidney.6 While involvement of the kidney may be a relatively late manifestation, after the cardiac injury initiating the processes leading to the clinical syndrome of heart failure, it is undeniable in the patient presenting with expansion of extracellular fluid volume and frank edema.


Before continuing to examine the body’s responses in heart failure, it is worth pausing and reiterating the remarkable fact that,despite the development of hugely successful treatments for heart failure, we still do not understand two of the most fundamental processes in the development of this clinical condition, that is, the “signal” that evokes the body’s response to pump dysfunction and how and where the signal (or signals) is sensed.


Returning to the responses to the failure to deliver oxygen adequately for the needs of the metabolizing tissues (assuming that is a key signal), these are protean and impossible to describe completely. Indeed, it would be true to say that almost everything measured in patients with heart failure is abnormal and very few things are completely normal.7 Identifying the key pathophysiological responses in heart failure is difficult and the history of medicine has taught us that mechanisms thought to be important today may come to be regarded as epiphenomena by tomorrow.7 Two attractive unifying and related hypotheses have, however, to date, stood the test of time. Harris and others proposed that heart failure can be thought of as akin to hemorrhage and the body’s response is similar, that is, directed at maintaining perfusion of vital organs.8–10 Francis, Cohn, Packer, and others focused on the array of neurohumoral abnormalities identified in heart failure, particularly those causing vasoconstriction (or perhaps, more accurately, redistribution of blood) and sodium and water retention.11,12 Key among those are activation of the reninangiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) and increased release of arginine vasopressin. Of course these neuroendocrine changes also occur in response to hemorrhage where their potential benefits are obvious.8–10 In heart failure caused by systolic dysfunction of the left ventricle at least, their sustained action is thought to be maladaptive and detrimental and that construct has probably been validated by the therapeutic success of RAAS and SNS inhibitors. This distinction between the temporary and beneficial effects of neurohumoral activation in hemorrhage and detrimental effects of sustained, long-term activation of the same in heart failure is important. It is a potential explanation, at least in part, of one other key characteristic of the heart failure state, that is, its progressive nature.13–16 In other words, patients with heart failure tend to show worsening of their condition over time, manifest as increasing symptoms hemodynamic deterioration and premature mortality. Key to the neurohumoral hypothesis is the belief that the neural, endocrine, paracrine, and autocrine systems chronically activated in heart failure indirectly (and directly) cause additional cardiac damage and pump dysfunction as well as vascular dysfunction contributing to circulatory failure. Other intercurrent cardiac events and even the metabolic, cellular, and molecular changes in the heart, per se, may also contribute to progression.13–16



The “hemorrhage” and “neurohumoral” hypotheses are attractive in other ways. For example, if one looks beyond the obvious vascular and renal actions of the neurohumoral pathways described, the hemorrhage hypothesis would lead one to postulate that the RAAS and SNS should also encourage coagulation (to stop bleeding), wound healing (scarring or fibrosis, for the same reason), erythropoiesis (to restore lost red blood cells and hemoglobin), and also promote anti-infective and inflammatory responses (to prevent infection as a result of breach of the skin).17–20 Although unrecognized at the time when Harris and others were developing their hypotheses, more and more evidence has emerged that the RAAS and SNS do indeed have this wide range of effects.17–20 Indeed, the systemic response to injury and hemorrhage is so ancient in evolutionary terms, and teleologically so fundamental to survival of the organism there are almost certainly multiple, overlapping, and redundant pathways involved.8–10 The obvious extrapolation, if this is true, is that there may also be other therapeutic targets offering the potential success of the tools we now have to block the RAAS and SNS. Of course, this broader understanding may also help explain some of the unanticipated actions of inhibitors of the RAAS and SNS such as the anti-infarction effect of angiotensin-converting enzyme (ACE) inhibitors and the reduction in hemoglobin associated with the use of these drugs.



HEART FAILURE: A PRACTICAL APPROACH TO TREATMENT


Although plausible and attractive, as outlined above, the hemorrhage hypothesis does not completely explain the neurohumoral picture of heart failure. We now know, for example, that blood natriuretic peptide concentrations are elevated in heart failure but reduced in hemorrhage.21 Indeed, arguably, the heart failure state results in a neurohumoral profile more akin to sustained exertion than hemorrhage.22


Of course many other profound metabolic, cellular, and molecular changes occur in the heart and other tissues in heart failure, and these are not characteristic of hemorrhage where the occurrence of (and responses to) neurohumoral activation persists over a relatively short period of time compared to the patient with chronic heart failure and where the heart is fundamentally healthy.13–15,23


Although the neurohumoral pathways alluded to earlier clearly have powerful renal actions, which lead to sodium and water retention, it is not at all clear whether those are a complete explanation for the way in which the kidney behaves in heart failure and, despite being pivotal in the development of the key manifestations of heart failure, that is, dyspnea and edema, our understanding of the workings of the kidney in heart failure is very limited.6,24


While I have implied that dyspnea is directly related to sodium and water retention, I do not mean to suggest that fluid overload is its essential cause. It probably is not, though dyspnea is very likely when fluid overload is present. It may still occur in patients without clinically obvious fluid overload and its causes remain elusive, though many mechanisms have been postulated (e.g., abnormal skeletal muscle metabolic or chemoreceptor activation) and even probably disproved (e.g., raised pulmonary capillary wedge pressure).25–27 Fatigue, the other symptom said to be characteristic of heart failure (though I am not so sure it is actually caused by heart failure), is even more mysterious in origin.25–27


So where are we so far with the definition of heart failure? We know it is a clinical syndrome arising from many different causes. There is an underlying cardiac abnormality (unless there is an alternative explanation such as anemia); though not all patients with the cardiac abnormality in question may have the syndrome of heart failure. The key manifestations of the syndrome are dyspnea, fatigue, and congestion, although sodium and water retention may not occur for a long period (even years) after a cardiac abnormality has been identified. We know that neurohumoral activation occurs, though the degree and extent of this may vary according to the underlying cardiac abnormality, symptom severity, and concomitant treatment.28–30 While neurohumoral activation is important in the pathophysiology of heart failure, multiple other abnormalities are also measurable and may or may not be important. In many, if not most, patients, the kidney retains an excessive amount of sodium and water.


Modern clinical definitions of heart failure have attempted to integrate these key features. For example, the European Society of Cardiology requires (a) the presence of typical symptoms and signs; (b) evidence of a cardiac abnormality (identified by an electrocardiogram or cardiac imaging) or, alternatively, evidence of neurohumoral activation reflecting atrial or ventricular “distress,” that is, elevation in concentration of a blood natriuretic peptide; and (c) if there is remaining doubt, a therapeutic response to treatment, for example, improvement in symptoms with a diuretic (Fig. 1-1).31


So far, I have adhered to the traditional clinical notion of heart failure as a syndrome, that is, by definition a symptomatic condition. Of course, it has been long recognized by clinicians (and experimental physiologists) that an asymptomatic (or perhaps presymptomatic) state of impaired pump function can exist and may be associated with some but not all of the characteristic abnormalities of the symptomatic state, for example, reduced functional capacity and neurohumoral activation (albeit to a lesser extent).28 This is true for both myocardial disease (e.g., asymptomatic left ventricular systolic dysfunction after myocardial infarction) and valve disease. Whether these patients should be described as having heart failure is a moot point. Clearly they do not have a “syndrome,” which, by definition, requires the presence of symptoms. Perhaps there is merit in differentiating between heart failure and “symptomatic heart failure,” the latter corresponding to the traditional clinical syndrome and the former a broader population including asymptomatic patients. The advantage of this expanded classification is that it highlights the opportunity to prevent (and importance of preventing) progression to the symptomatic state with all that it entails in terms of well-being, morbidity, and mortality.32 An expanded approach of this type has been advocated in recent American College of Cardiology and American Heart Association guidelines (Fig. 1-2).33 The potential range of cardiac abnormalities and assessment of their severity and functional significance pose real difficulties. What degree of hypertrophy or what level of ejection fraction merits intervention, assuming those measures can even be made accurately and reproducibly? Here again, measurement of blood natriuretic peptides may act as a guide, though this is still a subject of research, and the screening for and treatment of asymptomatic cardiac disease using natriuretic peptides is not yet advocated in routine clinical practice.


In summary, to the clinician, heart failure traditionally has been recognized as a syndrome characterized by dyspnea, fatigue and congestion, caused by an abnormality of the heart, and associated with At risk for heart failure Heart failure an array of systemic pathophysiological abnormalities including, notably, neurohumoral activation and renal sodium and water retention. In many patients, an asymptomatic phase may precede development of the symptomatic syndrome and once the symptomatic state has developed, progression leading to symptomatic worsening and death is typical.


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