An alternative approach to understanding the pathophysiological mechanisms of chronic heart failure

International Journal of Cardiology 154 (2012) 102–110

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International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d

Review

An alternative approach to understanding the pathophysiological mechanisms of chronic heart failure David H. MacIver ⁎, Mark J. Dayer Department of Cardiology, Taunton & Somerset Hospital, Musgrove Park, Taunton, Somerset, TA1 5DA, UK

a r t i c l e

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Article history: Received 26 September 2010 Received in revised form 16 March 2011 Accepted 13 May 2011 Available online 21 June 2011 Keywords: Heart failure Stroke volume Ejection fraction End-diastolic volume Pathophysiology Pathogenesis

a b s t r a c t No single well established hypothesis for the mechanisms of heart failure currently exists. Those definitions that do exist are either not universally applicable or are not exclusive to heart failure. The pathogenesis of heart failure has been considered by some to be too complex to define with multiple pathophysiological processes being implicated. The many clinical and neurohumoral features of heart failure may be more dependent on the severity of the condition and its speed of onset rather than its etiology. This suggests a potential single common pathway or pathogenic mechanism in all forms of heart failure regardless of cause. This viewpoint uses the framework of myocardial mechanics and energetics to propose an alternative, simplified definition and unifying hypothesis for the pathogenesis of chronic heart failure. Chronic heart failure may be understood as follows. Cardiac output and stroke volume are determined by the tissues' requirements; the ejection fraction is determined by both myocardial shortening and degree of end-diastolic wall thickness; the end-diastolic volume is determined by the requirement to normalize stroke volume. We will argue that chronic heart failure can be viewed as a condition where the dominant compensatory mechanism is through regulation of ventricular end-diastolic volume. Consequently, in conditions where there is a fall in tissue perfusion, stroke volume and tissue perfusion are returned toward normal predominantly via this feedback mechanism. It is important for researchers, clinicians and their patients that we strive for a comprehensive, inclusive and unambiguous unifying hypothesis for pathophysiological mechanisms of heart failure. © 2011 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Heart failure (HF) is, like so many other concepts, a “much used but ill-defined term”[1]. It is also much misunderstood. According to the AHA/ACC, HF is defined as a clinical syndrome that is characterized by specific symptoms (dyspnea and fatigue) and signs (edema, râles) on physical examination. There is no single diagnostic test for HF and therefore it is largely a clinical diagnosis that is based on a careful history and physical examination [2]. The European Society of Cardiology adopts a similar approach: “In recent years, most definitions have emphasized the need for both the presence of symptoms of HF and physical signs of fluid retention”[3]. Heart failure is inevitably a clinical diagnosis only because the pathophysiological mechanisms are not fully understood. As symptoms are inherently subjective it is difficult to find absolute cut-offs. However that does not mean that the syndrome cannot be understood or labels applied. It simply means that there will always be grey cases.

Abbreviations: HF, Heart failure; HFPEF, Heart failure with a preserved (normal) ejection fraction; HFREF, Heart failure with a reduced ejection fraction; LVEDV, Left ventricular end-diastolic volume; LVEF, Left ventricular ejection fraction. ⁎ Corresponding author. Tel.: + 44 1823 342130; fax: + 44 1823 342709. E-mail address: [email protected] (D.H. MacIver). 0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2011.05.075

The principal function of the heart is to convert chemical energy into mechanical energy (pressure) in order to produce blood flow (kinetic energy). This enables the provision of adequate nutrients (including oxygen) and facilitates the removal of waste products from the tissues. When abnormalities cause an inappropriate cardiac output, physiological feedback mechanisms are invoked to return cardiac output, and tissue perfusion, back to normal. The pathophysiological processes underlying heart failure have been debated for over a century with no clear consensus emerging [4]. James Hope originally proposed the backward failure hypothesis: whereby the ventricle fails to discharge its contents, blood accumulates and pressure rises in the atrium and ultimately the venous system emptying into it [5]. Over the next 150 years most authors supported the forward failure hypothesis, the failure of the heart to pump adequate blood to the tissues [6–8]. The backward failure hypothesis was reintroduced in 1988 to explain heart failure with a preserved ejection fraction (HFPEF)[9], a poorly understood condition which has resulted in confusion. As ejection fraction was, by definition, preserved in HFPEF, it was assumed that systolic function was also normal and consequently alternative explanations for the heart failure were sought. We will demonstrate that a normal LVEF in HFPEF does not necessarily equate to normal systolic myocardial function.

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Current views implicate both the backward and the forward failure hypotheses as mechanisms of heart failure. The most commonly cited definition of heart failure is “the pathophysiological state in which the heart is unable to pump blood at a rate commensurate with the requirements of the metabolizing tissues or can do so only from an elevated filling pressure” [10]. However, individuals with heart failure often have relatively normal stroke volumes [11,12]. The former part of this definition better describes low output states as may be seen in hypotension, cardiogenic shock and patients with severe heart failure (Class IV). The latter part of the definition invokes raised filling pressure as the main compensatory mechanism. In fact, the Frank– Starling mechanism is exhausted in chronic heart failure [13–16] and so an elevated filling pressure itself cannot be responsible for the normalized stroke volume. Coats et al. turned to the periphery when they proposed the muscle hypothesis to explain the mismatch between ejection fraction, hemodynamics and symptoms [17]. Figures demonstrating the mismatch of peak oxygen uptake and ejection fraction were contrasted with those demonstrating the close correlation between peak oxygen uptake and skeletal muscle mass. A wealth of literature has accrued describing the impact of heart failure on multiple organ systems. We wish to challenge the commonly held view that tissue perfusion is determined by the heart and the tissues simply receive what they are given. We support the view that feedback mechanisms from the periphery regulate cardiac output and that the left ventricle may adapt to loading conditions [18]. We propose that heart failure only occurs when perfusion to the tissues (e.g. brain and kidneys) is limited, often initially only on exercise, but in severe cases at rest. Heart failure becomes clinically apparent when the limitation is recognized by the patient and perceived as abnormal. As a consequence of reduced tissue perfusion additional changes occur such as neurohumoral activation. These secondary abnormalities may then “feed forward” and exacerbate the syndrome of heart failure itself. The precise manifestations of heart failure will depend on the etiology and severity of ventricular dysfunction, the rapidity of onset, the duration of the condition, the body's response to the underlying situation and the effect of medication. The clinical features of heart failure are similar despite its multiple causes [19] suggesting a potential unifying pathophysiological mechanism. As the features are not dependent on its etiology there may be a single process involved with a cascade of secondary and tertiary phenomena. We propose that heart failure in all its forms can be largely understood by considering heart rate, ejection fraction and end-diastolic volume. Cardiac output is fundamentally dependent on these three measures. Cardiac output is the product of stroke volume and heart rate. Stroke volume is dependent on ejection fraction and end-diastolic volume. An ejection fraction of 20% in a dilated ventricle may produce an equivalent stroke volume to a normally sized ventricle with an ejection fraction in the normal range. Of note, many of the potential compensatory mechanisms such as the force-frequency relationship [20,21] as well chronotropic responses are severely blunted in chronic heart failure [22,23]. Simple mathematics produces Fig. 1a. This shows the ejection fraction plotted against the left ventricular end-diastolic volume indexed to body surface area for a constant cardiac index at different heart rates. Similar findings have been demonstrated in heart failure patients (Fig. 1b). The same cardiac index can be achieved by varying LVEDV, heart rate or LVEF. What can be seen is that to maintain a preserved cardiac output at a given heart rate, as ejection fraction falls the end-diastolic volume must increase. If heart rate falls, either ejection fraction must rise or the end-diastolic volume must increase, to maintain cardiac output. To achieve a higher cardiac output, for example on exercise, changes can occur to all of these variables; patients with heart failure have a reduced capacity to increase their cardiac output.

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Fig. 1. a. Ejection fraction vs. left ventricular end-diastolic volume indexed for body surface area at different heart rates (assuming a constant cardiac index of 2.33 l/min/m2 and no valvular regurgitation). Adapted from MacIver [75]. b. Actual relationship between LVEDV index and LVEF in individuals with heart failure.

There has been much confusion caused by an obsession with LVEF at rest. We argue that a careful review of more recent data demonstrate that a normal ejection fraction does not equate with normal myocardial systolic function, neither does it imply a normal exercise-related response, and we hypothesize that all forms of heart failure can be understood by appreciating myocardial function in its totality. Let us turn first to examine the case of heart failure with a preserved ejection fraction (HFPEF).

2. Heart failure with a preserved ejection fraction HFPEF is a particularly difficult condition to comprehend [24]. It has really only been in recent years that it has been clearly understood that the heart can appear to function normally, as defined by ejection fraction, yet clinical heart failure can still be present. When ejection fraction is normal it has been assumed that systolic function is also normal and consequently alternative explanations for the syndrome of heart failure have been sought. The term “diastolic heart failure” has been widely used to describe the sub-group of patients with heart failure and a normal ejection fraction where other cardiac or non-cardiac causes, such valvular and lung disease, have

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been excluded and when the primary abnormality is thought to be due to reduced left ventricular compliance [25]. 3. Determinants of measures of “diastolic dysfunction” Diastolic dysfunction is often defined as an abnormality of filling of the left ventricle due to abnormal relaxation or compliance. This may occur due to abnormalities of calcium handling, abnormal deposition (e.g. collagen) or due to infiltration (e.g. cardiac amyloid). Often in clinical practice diastolic dysfunction is assessed indirectly by either measuring the effects of abnormal filling pressures (e.g. blood flow Doppler studies including pulmonary venous and mitral valve flow) or by speed and distance of events such as myocardial movement (e.g. annular velocity E', ventricular untwisting etc.). Echocardiographic features of “diastolic dysfunction” have included the following [26]: a) decreased or slowed diastolic variables (e.g. longer mitral valve forward flow deceleration time, reduced E’ velocity, longer isovolumic relaxation time, reduced E wave velocity, increased A wave, reduced E/A ratio) and b) raised filling pressures (e.g. shortened deceleration time, increased E wave velocity, increased E/E’ ratio, shortened isovolumic relaxation time, pseudonormalization of E/A ratio, increased left atrial size, etc.). The features in a) only occur in mild diastolic dysfunction but those in b) only arise when filling pressures are high and are opposite to the effects anticipated in a). Therefore, we propose they do not exclusively indicate diastolic dysfunction. Further, if mitral annular systolic displacement is reduced then inevitably mitral annular diastolic displacement is reduced by the same amount. Likewise if mitral annular systolic velocities are reduced then diastolic velocities will also be similarly reduced [27]. It cannot be assumed that the changes brought about by raised filling pressures can be explained solely by diastolic dysfunction. For example, similar changes occur in heart failure with reduced ejection fraction (HFREF) and abnormal fluid challenges even in the absence of myocardial disease. Increased intravascular volume occurs in both HFREF and HFPEF and precedes other manifestations of chronic heart failure [28,29]. Furthermore venous pressure and end-diastolic pressures are still increased following death in heart failure [30]. Even pressure–volume loops are problematic since the expected abnormal end-diastolic pressure-volume relationship in HFPEF [31,32] does not always occur. This suggests that diastolic dysfunction by itself may not be the primary or even dominant physiological abnormality [11,33–35]. Although diastolic dysfunction certainly exists, many of the socalled diastolic function abnormalities described may be equally well explained by abnormalities of systolic function (i.e. contractile

dysfunction) and secondary to raised filling pressure per se. As measures of diastolic dysfunction are poorly understood the role of diastolic dysfunction in heart failure also remains inadequately characterized. We do not think that isolated diastolic dysfunction can be used to explain the dominant mechanism of heart failure in the majority of patients with HFPEF. Starling [6] did not think that Hope's original theory of backward failure [5] was plausible. Measures of “diastolic dysfunction” are not exclusive to patients with a preserved ejection fraction; they are more common, and often more severe, in patients with a reduced ejection fraction [36]. We argue that in fact, despite the preserved ejection fraction, there is important evidence of systolic dysfunction in this group of patients. Before we enter further into this discussion it is necessary to review a number of echocardiographic techniques. 4. Echocardiography and the evaluation of strain A full discussion of the principals and limitations of such imaging is beyond the scope of this article, but the interested reader is referred to Pellerin and colleagues [37]. In brief, strain is derived by measuring the deformation of myocardial tissue. Shortening or thinning of myocardium has, by convention, a negative value as a percent of starting length. Conversely, lengthening or thickening has a positive value. Strain rate measures the rate of such deformation. When performing an echocardiogram both strain and strain rate are now readily available and are derived from either Doppler measurement of tissue movement or by tracking speckles within the myocardium. Myocardial movement during systole and diastole is complex and reflects the fiber-orientation of the myocardium. There is so-called longitudinal movement of the ventricles, with the mitral valve annulus moving towards and away from the apex. This is principally thought to be caused by contraction of the longitudinal fibers in the subendocardium and subepicardium [38]. Circumferential strain results from shortening of the midwall circumferential fibers. Finally, radial strain reflects the myocardial wall thickening and is a consequence of both circumferential and longitudinal muscle fiber shortening (Fig. 2) [39]. 5. HFPEF and myocardial hypertrophy Heart failure with normal, or preserved, ejection fraction (HFPEF) is associated with concentric left ventricular hypertrophy and a relatively normal end-diastolic volume (Table 1) [11,32,35,40,41]. There are many different conditions which can lead to myocardial hypertrophy and symptoms of heart failure are common in all. End-

Mid-wall circumferential fibres

Radial strain

Circumferential strain

Longitudinal strain

Fig. 2. Differentiation of longitudinal, circumferential and radial strain. Myocardial contraction of long axis fibers results in longitudinal shortening and circumferential fiber contraction results in circumferential shortening. This results in radial thickening. Strain is a measure of shortening (negative strain) or thickening (positive strain) and is usually expressed as a percentage. Strain = L − Lo/Lo, where L = new length and Lo is original length.

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Table 1 Left ventricular mass and end-diastolic volume in hypertension and HFPEF. Data from Maurer et al. [11,35], Baicu et al. [40] and Lam et al. [32]. Most patients with HFPEF have significant concentric hypertrophy and a relatively normal end-diastolic volume. For example, cohort “a” had mild concentric hypertrophy, normal LVEDV and mild heart failure; cohort “b” had a mixed etiology with hypertension and a high incidence of coronary artery disease; Cohort “c” had “pure” HFPEF (mainly secondary to cardiac amyloid or hypertrophic cardiomyopathy), an end-diastolic volume of 8% less than their controls (not significant) and a left ventricular mass of 40% greater than their controls. Group

LV mass index (g/m2)

LVEDVI (ml/m2)

Stroke volume index (ml/m2)

Co

Pt

%Δ

Co

Pt

%Δ

Co

Pt

%Δ

Co

Pt

%Δ

↑BP ↑BP HFPEFa HFPEFb HFPEF HFPEFc HFPEF

78 89 89 72 78 72 82

87* 100* 102* 92* 98* 101* 114*

+ 12 + 12 + 15 + 28 + 26 + 40 + 39

63 67 67 53 63 53 58

62* 65ns 61ns 62* 69* 49ns 47*

−1 −3 −3 + 17 + 10 −8 −20

72 63 63 58 72 58 61

74* 65ns 62* 54* 72ns 50* 58ns

+3 +3 −2 −7 0 −14 −5

45 46 46 31 45 31 35

46ns 46ns 42* 33na 50* 25na 27na

+2 0 −9 +6 + 11 −19 −23

LVEF (%)

Reference

Maurer et al. [11] Lam et al. [32] Lam et al. [32] Maurer et al. [35] Maurer et al. [11] Maurer et al. [35] Baicu et al. [40]

*p b 0.05; ns: p N 0.05; na: p = significance not available; Co: control cohort; Pt: patient cohort; %Δ: %change from control group; ↑BP: hypertension.

diastolic myocardial wall thickness is arguably a crucial measure when understanding myocardial function. We will outline the evidence that a normal ejection fraction, particularly in the context of myocardial hypertrophy, does not equate to normal myocardial function. 6. Conditions in which myocardial hypertrophy occurs and underlying changes in strain Hypertension produces both myocardial hypertrophy and myocardial dysfunction. Hypertensive heart disease might best be referred to as hypertensive hypertrophic cardiomyopathy to emphasize the myocardial abnormalities in both diastole and systole. Despite a typically normal ejection fraction, significant systolic functional abnormalities of strain, strain rate and tissue Doppler have been demonstrated (Table 2) [12,42,43]. Conditions that cause pseudo-hypertrophic left ventricular disease due to infiltration (infiltrative hypertrophic cardiomyopathy) such as hemochromatosis, cardiac amyloid or Fabry disease also demonstrate significant contractile abnormalities despite the (usually) normal ejection fraction [44–46]. Sarcomeric hypertrophic cardiomyopathy is caused by abnormalities of the myocardial contractile proteins and manifests myocardial disarray and scarring [47]. Each of these three abnormalities would be expected to cause reduced myocardial contractility and yet the ejection fraction is usually normal, or may even be increased, except in the very end-stages. This predicted reduction in myocardial strain in hypertrophic cardiomyopathy despite the normal ejection fraction has been confirmed [48–51]. How can this contradiction of a preserved ejection fraction with important contractile abnormalities be explained in these conditions? An increase in end-diastolic left ventricular wall thickening leads to augmented absolute systolic thickening if myocardial shortening is constant (Fig. 3a and b); in the presence of contractile dysfunction,

absolute systolic wall thickening may be nearly normal (Fig. 3c). As the external volume of the left ventricle changes by only 3% during the cardiac cycle [52] the endocardial displacement, and therefore, ejection fraction, is preserved. The ejection fraction is simply a ratio of the stroke volume to end-diastolic volume and, has been shown using 3-dimensional mathematical modeling, to be determined by both myocardial shortening and the end-diastolic wall thickness (Fig. 4) [53,54]. It has been assumed that in HFPEF there is a compensatory increase in radial function [55] but this is not supported by the evidence (see Table 2). Although long-axis abnormalities in HFPEF are well recognized [42], there are fewer data on radial or midwall circumferential function in hypertensive-hypertrophic disease. However, abnormalities of midwall circumferential shortening have been documented despite normal endocardial circumferential shortening in hypertensive-hypertrophic disease due to a relatively greater contribution of wall thickening [56]. An increase in end-diastolic wall thickness explains the reduced midwall circumferential and long-axis shortening and yet normal ejection fraction [57]. In a cohort of patients with HFPEF, midwall fractional shortening in patients with heart failure was significantly less than controls despite mean endocardial fractional shortening being unchanged [58]. Wang et al. [43] and Tan et al. [59] showed reduced longitudinal and radial strain (with a trend toward reduced circumferential strain from −20% to −15%) in HFPEF. Recent data shows that stress-corrected midwall myocardial shortening is also reduced in HFPEF [60]. This suggests that the reduced myocardial shortening observed probably reflects true myocardial contractile abnormalities rather than due to an increased “afterload” and abnormally high systolic wall stress. The confusion arises because reduced long axis shortening with reduced midwall circumferential shortening (i.e. less negative strain) must cause a reduced radial strain. However, when the end-diastolic wall thickness is increased, the endocardial displacement is the same as normal and hence the ejection fraction is normal [61]. Thus the

Table 2 Resting peak systolic myocardial strain in heart failure and hypertrophic left ventricular disease. Note that longitudinal, circumferential and radial strains are generally reduced in patient groups. In hypertrophic myocardial disease ejection fraction is preserved. In HFREF strain is more severely reduced (also see Fig. 4). Group

cLVH Aortic Stenosis Hypertension Sarcomeric HCM HFPEF HFPEF HFPEF HFREF HFREF

Longitudinal strain (%)

Circumferential strain (%)

Radial strain (%)

LVEF (%)

Reference

Control

Patient

Control

Patient

Control

Patient

Control

Patient

−22.9 −20.3 −20.3 −20.3 −19.0 −20.9 −21.0 −19.0 −21.0

−17.9** −14.6** −17.2** −15.1** −12.0* −18.9* −16.0** −4.0* −9.6**

−23.7 −19.5 −19.5 −19.6 −20.0 na −26.4 −20.0 −26.4

−20.4** −15.2** −17.0 −16.8** −15.0 na −20.7 −7.0* −9.5**

+ 74.4 + 38.9 + 38.9 + 36.8 + 47.0 + 49.2 + 44.3 + 47.0 + 44.3

62.7** + 33.9ns + 34.4ns + 25.2** + 28.0* + 41.8* + 32.9** + 14.0* + 19.0**

77 62 62 67 64 62 na 64 na

70* 61ns 61ns 69ns 63ns 61ns N 50 24* na

na: data not available; ns: p N0.05; *p b 0.01; **p b 0.001; cLVH: concentric left ventricular hypertrophy; HCM: hypertrophic cardiomyopathy.

Mizuguchi et al. [85] Delgado et al. [86] Delgado [86] Serri et al. [51] Wang et al. [43] Tan et al. [59] Yip et al. [87] Wang et al. [43] Yip et al. [87]

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Results

Normal peak strain

Abnormal peak strain

-20% End-diastolic thickness (mm) End-systolic thickness (mm) Radial strain (%) Absolute wall thickening (mm)

9 14 56 5.1

13 20 56 7.3

17 27 56 9.6

Abnormal peak strain

-15% 21 33 56 11.8

9 13 38 3.5

13 18 38 5.0

17 24 38 6.5

-10% 21 29 38 8.1

9 11 23 2.1

13 16 23 3.1

17 21 23 4.0

21 26 23 4.9

Fig. 3. Effect of increased end-diastolic wall thickness on wall thickening. Theoretical cubes of myocardium in diastole (left) and systole (right) are shown. Compared with normal wall thickness of 9 mm (a), mild concentric hypertrophy (wall thickness 13 mm) leads to augmented radial wall thickening (b) and reduced myocardial shortening with hypertrophy results in normal absolute radial wall thickening (c). Note that if circumferential strain and longitudinal strain are reduced (less negative), radial strain (relative wall thickening) will also be reduced (less positive) despite the normal absolute wall thickening of 5 mm. Assumes myocardium is non-compressible elastomer; negative strain refers to circumferential and longitudinal % shortening. Adapted from MacIver [41]. Radial strain is determined by circumferential and longitudinal strain; absolute wall thickening and ejection fraction are determined by both radial strain and end-diastolic wall thickness [39].

paradox of reduced radial, circumferential and longitudinal strain in HFPEF but normal absolute radial thickening and, therefore, ejection fraction can be explained by the increased end-diastolic wall thickness (Fig. 4) [39,53]. A compensatory increase in radial function in HFPEF is a cognitive illusion and can be explained by the

Fig. 4. Relationship between myocardial shortening and left ventricular end-diastolic wall thickness. The left ventricular ejection fraction is determined by both end-diastolic wall thickness and myocardial shortening (adapted from MacIver [54] using mathematical modeling of left ventricular contraction). Each curve represents different strain values: Normal strain (circumferential −19.0%, longitudinal −17.5%), mildly reduced (−14.0%, −10.8%), moderately reduced (−9.0%, −5.6%) and severely reduced (−6.0%, −3.2% respectively).

“augmented” absolute radial thickening (end-diastolic thickness minus end-diastolic thickness). We have demonstrated that the terms left ventricular ejection fraction and left ventricular function are not synonymous. In the context of concentric hypertrophy one can see normal absolute radial thickening despite the presence of reduced myocardial shortening. This results in a normal ejection fraction and hence the illusion of normal pump function. The finding of reduced strain in the presence of a normal ejection fraction has led to the suggestion that the ejection fraction ought to be adjusted for the degree of hypertrophy by using a “corrected” ejection fraction (EFc)[61]. The end-diastolic volume at rest tends to be relatively normal in hypertrophic-hypertensive heart disease. This has been explained by the inability of the left ventricular wall to stretch because of the stiffening. However, this would not explain the subnormal values of end-diastolic volume seen in some individuals with HFPEF. We have not explained, however, why symptoms of heart failure may occur in this situation—after all the ejection fraction is normal at rest. HFPEF rarely results in cardiogenic shock and typically manifests itself as a reduction in exercise capacity or fluid retention. Observations have shown that the expected increase in left ventricular ejection fraction, stroke volume, cardiac index, cardiac output and end-systolic elastance during exercise in patients with HFPEF is not as great as in controls [22,59,62]. Furthermore, there is a diminished contractile response to pacing in patients with concentric hypertrophy compared to controls [63]. As in HFREF, patients with HFPEF have a blunted chronotropic response to exercise [22,62]. Recent interesting data show that the resting abnormalities of long-

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axis systolic and diastolic function, rotation and systolic radial strain become greater during exercise compared with controls [59]. Three recent studies have confirmed that stroke volume and cardiac index fail to increase with exercise compared to controls in HFPEF [64–66]. Thus patients with HFPEF have a normal ejection fraction in the context of reduced systolic function and a reduced contractile reserve. Let us examine HFREF next. 7. Heart failure with a reduced ejection fraction Heart failure with reduced ejection fraction (HFREF) is diagnosed when the ejection fraction is less than 50% and heart failure signs or symptoms are present. Without signs and symptoms it is better termed asymptomatic left ventricular dysfunction. In these situations abnormalities of systolic function are more obvious compared with HFPEF. There have been a number of efforts to explain the disparity between ejection fraction and symptoms. This is perhaps based on a number of misconceptions. One misconception is that stroke volume is typically reduced. It is often assumed that most cases of chronic heart failure are associated with a low cardiac output and reduced stroke volume. This sort of teaching is particularly easy to accept in patients with a reduced ejection fraction. The inconvenient truth is that stroke volume and cardiac output are often relatively normal (Table 3). The reason for this can be understood mathematically: if the enddiastolic volume is increased a reduced ejection fraction will result in an equivalent stroke volume to a normal ejection fraction in a normally sized ventricle (Fig. 1a). Conversely, if the end-diastolic volume is reduced in a grossly hypertrophied ventricle the ejection fraction must rise to maintain stroke volume. The latter situation is not infrequently seen in patients with more extreme hypertrophic cardiomyopathy. This inverse relationship has been demonstrated in heart failure patients (Fig. 1b)[67]. 8. Determinants of end-diastolic volume It seems reasonable to suppose that the increased ejection fraction is a consequence of hypertrophy in hypertrophic cardiomyopathy. It is a little more difficult to understand what determines end-diastolic volume in HFREF. Is remodeling a reactive (i.e. adaptive) or passive (and purely maladaptive) process? A dilated left ventricle is often regarded as a purely adverse event reflecting a weakness of the ventricular wall in part related to the toxic effect of neurohormones (the neurohumoral hypothesis—Fig. 5) [68]. Current opinion has recently been reviewed and left ventricular remodeling is seen “as a mechanism for worsening heart failure” [69]. However, the left ventricle dilates in the presence of valvular regurgitation, astronauts [70], endurance athletes [71] and pregnancy [72] even in the absence of myocardial disease. These changes also reverse following removal of the stimulus suggesting that this remodeling can be an adaptive and reactive physiological response. Table 3 Stroke volume and cardiac output in chronic heart failure. Stroke volume and cardiac output/index are not reduced in stable heart failure. Values may even be increased perhaps related to anemia [11], valvular regurgitation [88], etc. in heart failure groups. Variable

Control

HFPEF

HFREF

p

Comments

SV (ml) SVI (ml/m2) CI (l/min/m2) SVI (ml/m2) SVI (ml/m2) SV (ml) CO (l/min)

51.5 45 2.8 na 40 62 4.2

54.3 50 3.4 35 na 73 4.8

52.2 na na 36 46 na na

ns b0.05 b0.05 na na b0.01 b0.01

No HR data [12] ↑Cr, ↓Hb [11] ↑Cr, ↓Hb [11] HR 76/77 bpm [89] LVEF 68 vs. 46% [88] LVEF 62 vs. 61% [59] LVEF 62 vs. 61% [59]

ns: non-significant; na: not available; SV: stroke volume; HR: heart rate; SVI: stroke volume index; CI: cardiac index; Cr: creatinine; Hb: hemoglobin; bpm: beats per minute; LVEF: left ventricular ejection fraction.

Fig. 5. Potential mechanism of regulation of left ventricular volume. Commonly presumed mechanism on left. Proposed mechanism on right.

In the acute phase following a myocardial infarction, or as a consequence of acute myocarditis, there is a reduction in ejection fraction but, initially, no change in end-diastolic volume and so stroke volume is also reduced. Stroke volume is also reduced in acute exacerbations of HFPEF [73]. In the early stages heart rate is typically increased to normalize cardiac output (Fig. 1a). Tachycardia is relatively energetically inefficient [74], however, and over time, ventricular dilatation occurs [54,75] allowing the heart rate to fall; most physiological systems will tend to work at the lowest energy levels necessary for their needs. Following acute myocardial infarction there is often infarct expansion (hours to days) followed by sarcomere growth in series (over days to weeks) in the non-infarcted areas [76]. The mechanism of (auto)regulating end-diastolic volume is unknown but a suggested theory may be as follows. Acute myocardial damage would result in a temporary fall in stroke volume, reduced tissue perfusion, neurohumoral activation, fluid retention and increased filling pressures. The consequence would be ventricular dilatation and a normalization of stroke volume (Fig. 5). If the stroke volume were higher than physiologically necessary, an increased pressure diuresis would result in a fall in filling pressures and a reduction in end-diastolic volume. Therefore, the end-diastolic volume would be appropriate for the stroke volume and ejection fraction. We propose that the stroke volume is regulated by changes in LVEDV for a given LVEF. Gradual myocardial damage, as occurs in hypertension, would result in concomitant adaptive remodeling in order to maintain the stroke volume. There will of course be mechanical limits on the ability of the heart to remodel which will impinge upon these physiological mechanisms. This new hypothesis proposes that in developing heart failure the primary abnormality is that stroke volume falls below the resting metabolic needs (acute or decompensated chronic HF) and compensatory mechanisms (predominantly remodeling) returns stroke volume toward the tissues needs (Fig. 6). As myocardial disease often occurs progressively, the remodeling also develops gradually and apparently concurrently. In HFPEF the ejection fraction is, by definition, normal despite the reduced myocardial strain (Table 2) and so, if the stroke volume is normalized, the end-diastolic volume must also be normal. This remodeling hypothesis would explain the disappointing results of the Batista operation, extra-cardiac support mesh implantation and ventricular reduction surgery in HFREF [77]. A reduction in end-diastolic volume by surgical means would be predicted to cause an acute fall in stroke volume, hence decompensation and an adverse prognosis [75]. In more severe forms of heart failure where compensatory remodeling is inadequate, additional changes may occur in the

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Fig. 6. A schema to understand heart failure. This figure shows the single early pathological process (primary changes) of reduced stroke volume/cardiac output less than the requirements of the metabolizing tissues. Initial compensatory response (secondary) is shown. It is proposed that the dominant compensatory mechanism (tertiary) in chronic stable heart failure is normalization of stroke volume through regulation of end-diastolic volume. This is associated with adverse and maladaptive processes. The hemodynamic consequences and likely clinical picture are presented.

periphery. Perhaps this is best seen in skeletal muscle. Initially there is likely to be deconditioning due to reduced exercise. If heart failure worsens, and inflammation becomes more dominant, cachexia is seen and then changes associated with this can be observed in the muscles. This approach can explain the differences seen in peripheral skeletal muscle (reduced work) and the diaphragm (increased work) in patients with heart failure and the occurrence of specific muscle changes associated with the disease process when heart failure is more advanced [78–81]. 9. Heart failure in the context of normal myocardial function Using this paradigm it is possible to review different forms of heart failure from its perspective (Fig. 6). The heart failure syndrome in congenital heart disease has been reviewed [82]. For example, infants with an atrial septal defect and no pulmonary hypertension develop heart failure despite having normal left ventricular performance. From the alternative viewpoint this may be explained as follows. The left to right atrial shunt initially results in reduced left ventricular filling and stroke volume, with reduced tissue perfusion, followed by fluid accumulation, increased right ventricular volume, greater right ventricular stroke volume and finally normalization of left ventricular filling and stroke volume. Valvular heart disease due to either a regurgitant or stenotic lesion would result in a tendency for the effective “forward” stroke volume to fall; compensatory mechanisms such as dilation or concentric hypertrophy respectively would maintain the normal forward stroke volume. In arterio-venous malformations, there is insufficient peripheral perfusion, “tissue input,” because of a steal phenomenon. Therefore, the cardiac output and left ventricular stroke volume must increase to supra-normal values to normalize perfusion. In thyrotoxic heart

disease there is a combination of increased metabolic demand, myocardial toxicity and arrhythmias. The latter two would lead to a reduction in stroke volume and the former to an increased tissue perfusion requirements (high output failure) leading to relative tissue hypoperfusion, fluid retention and remodeling. Constrictive pericarditis may be explained by a restricted enddiastolic volume, a reduced stroke volume and fluid retention (Fig. 6). As the end-diastolic volume is unable to increase to normalize the stroke volume there is a poor prognosis and a limited response to pharmacological therapy. Similar physiology may exist in the very rare example of true restrictive cardiomyopathy where systolic function is thought to be entirely normal but there is an abnormality of compliance without any left ventricular hypertrophy. The reduced stroke volume produced by the reduced end-diastolic volume leads to fluid retention followed by an increased end-diastolic pressure. Physiologically this is very similar to constriction. Similar arguments may be applied to the right ventricle in other congenital and acquired abnormalities that result in the heart failure syndrome. For example right ventricular muscular diseases would result in reduced left ventricular filling pressure, fluid retention, rising right sided filling pressures, right ventricular dilatation, normalization of right ventricular stroke volume and a restoration of homeostasis. We have deliberately avoided discussing septic shock. This is a far more complex entity, and although it shares some features of highoutput cardiac failure there is often evidence of myocardial damage and complex changes within the vasculature. 10. The extra-cardiac manifestations of heart failure There is no question that heart failure can be regarded as a complex multi-system disease and the effects can be observed in

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many organ systems. It is not simply a case that heart failure causes changes in these systems—the impact on the organ systems may feedback and exacerbate the syndrome itself [17], and treatment directed to these manifestations may be beneficial [83]. A full discussion of the impact of heart failure on the periphery is beyond the remit of this article, and the interested reader is referred to articles such as those by Clarke et al. [84]. We simply wish to suggest that in true heart failure it is damage to the heart which results in the effects on other organ systems initially, although we recognize that a vicious circle may be set up. 11. Conclusions We propose that the primary abnormality in all heart failure syndromes, regardless of the cause, is a relative reduction in tissue perfusion by a number of different processes (Fig. 6). Feedback mechanisms from the tissues, particularly the brain and kidneys, regulate end-diastolic volume in an attempt to normalize the resting cardiac output. The dominant compensatory mechanism that leads to a normalization of tissue perfusion is the regulation of end-diastolic ventricular volume. It should be underlined that this normalization of stroke volume occurs in a “compensated” state (for example with reduced myocardial strain) in chronic stable heart failure. Furthermore, both diastolic and systolic abnormalities are likely to coexist whenever there is important myocardial disease. In addition, the failure to increase cardiac output appropriately with exertion is a crucial determinant of symptoms. This novel hypothesis suggests a single primary and early common pathway in heart failure and allows for the multiple complex secondary/tertiary “epiphenomena,” such as neurohumoral activation. We would like to emphasize that a normal ejection fraction may not equate to normal systolic function, as it is possible to have a preserved ejection fraction in the setting of an abnormal myocardial shortening and concentric left ventricular hypertrophy. The preservation of left ventricular ejection fraction is directly related to the presence of concentric hypertrophy in HFPEF. As such we propose a potential alternative, simpler and inclusive unifying hypothesis for the pathophysiological mechanisms of chronic heart failure. Acknowledgements The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [90]. References [1] Pirsig RM. Zen and the art of motorcycle maintenance. New York: Bantam Books; 1984. [2] Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 2005;112:e154–235. [3] Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008. Eur Heart J 2008;29:2388. [4] McMurray J. What is heart failure? In: Abraham W, Krum H, editors. Heart failure. A practical approach to treatment. New York: McGraw Hill Medical; 2007. p. 1–9. [5] Hope J. A treatise on the diseases of the heart and great vessels; 1832. [6] Starling EH. Arris and Gale Lectures on the physiology of lymph formation. Lancet 1894;143:785–8. [7] Mackenzie J. Disease of the Heart. 3rd ed. Oxford Medical Publications; 1913. [8] Harris P. Congestive cardiac failure: central role of the arterial blood pressure. Br Heart J 1987;58:190–203. [9] Kessler KM. Heart failure with normal systolic function: Update of prevalence, differential diagnosis, prognosis, and therapy. Arch Intern Med 1988;148: 2109–11. [10] Libby P, Bonow RO, Mann DL, Zipes DP. Braunwald's heart disease. A textbook of cardiovascular medicine8 ed. Philadelphia: Saunders Elsevier; 2007.

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