Journal of Cardiac Failure Vol. 13 No.

7 2007

Review Articles

Systolic and Diastolic Heart Failure: Differences and Similarities

KANU CHATTERJEE, MB, FRCP, FCCP, FACC, FAHA, MACP,1 AND BARRY MASSIE, MD, FACC2
San Francisco, California

ABSTRACT Background: Diastolic heart failure (DHF) and systolic heart failure (SHF) are 2 clinical subsets of the syndrome of chronic heart failure that are most commonly encountered in clinical practice. Methods and Results: The clinically overt DHF and SHF appear to be 2 separate syndromes with distinctive morphologic and functional changes although signs, symptoms, and prognosis are very similar. In DHF, the left ventricle is not dilated and the ejection fraction is preserved. In contrast in SHF, it is dilated and the ejection fraction is reduced. The neurohormonal abnormalities in DHF and SHF appear to be similar. The stimuli and the signals that ultimately produce these 2 different phenotypes of chronic heart failure remain, presently, largely unknown. Conclusions: Although there has been considerable progress in the management of SHF, the management of DHF remains mostly empirical because of lack of knowledge of the molecular and biochemical mechanisms which produce myocardial structural and functional changes in this syndrome. Further research and investigations are urgently required. (J Cardiac Fail 2007;13:569e576) Key Words: Systolic heart failure, diastolic heart failure, remodeling, function.

Diastolic heart failure (DHF) and systolic heart failure (SHF) are 2 clinical subsets of the syndrome of heart failure that are most frequently encountered in clinical practice. That these 2 forms of heart failure exist was recognized by Dr. Fishberg1 almost 70 years ago, as reported by Katz and Zile in a recent editorial.2 Dr. Fishberg wrote those forms of cardiac insufciency which are due to inadequate diastolic lling of the heart (hypodiastolic failure) [and] the far more common ones in which the heart lls adequately but does not empty to the normal extent (hyposystolic heart failure). However, confusions and controversies regarding the denitions, pathophysiology, prognosis and management of DHF and SHF continue.

Denitions and Diagnosis In the Webster Dictionary diastole is dened as the dilatation of the heart with blood: opposed to systole, or contraction. Conventionally, the closure of the aortic valve is regarded to indicate the onset of diastole as it indicates the onset of ventricular relaxation phase.3 Because left ventricular ejection inuences relaxation and the rapid lling, it has been suggested that these phases should be considered phases of systole.4 The most commonly accepted view, however, is that the rapid lling phase is part of diastole.5 Several denitions of DHF have been proposed. One denition is a condition resulting from an increased resistance to lling of one or both ventricles leading to symptoms of congestion due to an inappropriate upward shift of the diastolic pressure-volume relation (that is, during the terminal phase of the cardiac cycle).4 Another proposed denition is that diastolic heart failure is a condition in which the ventricular chamber is unable to accept an adequate volume of blood during diastole at normal diastolic pressures and at volumes sufcient to maintain an appropriate stroke volume.6 These denitions describe the functional abnormalities, but cannot be applied in clinical practice. Many clinical denitions of diastolic heart failure have been suggested. Zile and Brutsaert6 proposed a denition, which is a clinical syndrome characterized 569

From the 1Cardiology Division, University of California, San Francisco and 2Cardiology Division, Veterans Affairs Medical Center, University of California, San Francisco. Manuscript received December 12, 2006; revised manuscript received April 17, 2007; revised manuscript accepted April 17, 2007. Reprint requests: Kanu Chatterjee, MB, Director, Chatterjee Center for Cardiac Research, Cardiology Division, University of California, San Francisco, 505 Parnassus Avenue, M-1182, San Francisco, CA 941430124. This manuscript has been published, in part, in Cardiology Rounds, a publication of Brigham and Womens Hospital, December 2005, Volume 9, Issues 9 and 10. 1071-9164/$ - see front matter 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2007.04.006

570 Journal of Cardiac Failure Vol. 13 No. 7 September 2007 by the symptoms and signs of heart failure, a preserved ejection fraction (EF), and abnormal diastolic function. Other denitions such as heart failure with preserved systolic function or heart failure with normal or near normal ejection fraction have also been used. Several denitions of systolic heart failure also exist. In 1933, Sir Thomas Lewis dened heart failure as a condition in which the heart fails to discharge its contents adequately.7 In 1980, Dr. Braunwald described heart failure as 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.8 Although these denitions describe the pathologic mechanisms, it is difcult to employ in clinical practice. Thus it is preferable to use the terms diastolic and systolic heart failure as these denitions describe the principal mechanisms.
Incidence, Prevalence, and Prognosis

The incidence and prevalence of both SHF and DHF is considerable and increasing.12,13 The recent epidemic increase in heart failure in older population appears to be related both to increase in the incidence and improved survival.14 The incidence of systolic and diastolic heart failure has been reported to be 61% to 68% and 16% to 39%, respectively.15 The cross-sectional population echocardiographic studies have reported that of patients diagnosed with heart failure, 40% to 71% have DHF.15
Natural History of Asymptomatic Systolic and Diastolic Dysfunction

Systolic and Diastolic Dysfunction and Clinical Heart Failure Systolic dysfunction from impaired contractile or pump function and diastolic dysfunction from impaired ventricular relaxation, compliance or lling are not always associated with clinical heart failure characterized by signs and symptoms of low cardiac output or of congestion. Furthermore, in SHF, diastolic dysfunction as assessed by changes in the ventricular lling features is common, particularly in advanced heart failure. In diastolic heart failure, left ventricular systolic performance, function and contractility in general, remain normal.9 In some studies, long-axis systolic dysfunction has been observed.10

Asymptomatic left ventricular systolic dysfunction constitutes Stage B systolic heart failure.16 The prevalence of Stage B systolic heart failure in the community is between 3% and 6%.17 The risk of development of symptomatic heart failure is reported to be between 5.1% and 10.5%.17e21 The echo-Doppler studies have reported that patients with asymptomatic left ventricular diastolic dysfunction have a higher incidence of all-case mortality adjusted for age, sex, and ejection fraction.12 Mild diastolic dysfunction was associated with 8.3-fold, and moderate-to-severe dysfunction with 10.2-fold increased risk of mortality.12
Natural History in Symptomatic Patients

Diagnosis Based on the proposed denitions, it appears that for establishing the diagnosis of DHF or SHF, it is only necessary to measure left ventricular ejection fraction after conrming the presence of heart failure. If ejection fraction is preserved it is DHF, and if reduced it is SHF. It is highly desirable to establish the normal range of ejection fraction for any technique employed, preferably under similar loading conditions. It should be appreciated that signs and symptoms, radiologic and electrocardiographic ndings and neurohormonal prole cannot distinguish between DHF and SHF.6,11
Is Cardiac Catheterization Necessary?

The overall mortality of symptomatic patients with DHF or SHF is very similar22,23 and is related to the functional class. In patients with New York Heart Association Class II and III DHF, an annual mortality rate of 3.8% was observed.24 In patients who required hospital admissions for treatment, 1-year all cause death was 27% in DHF and 36% in SHF25 (Fig. 1).
Mode of Death

Coronary angiography is occasionally indicated when myocardial ischemia is strongly suspected, irrespective of type of heart failure. Similarly, endomyocardial biopsy is rarely necessary to establish the etiology of heart failure. Cardiac catheterization is not necessary to assess ejection fraction, contractile function, or diastolic functions.

In systolic heart failure approximately 50% of deaths are sudden and the rate of sudden death in systolic heart failure is 6 to 9 times higher compared with that in the general population.26 Interestingly, with the increased severity of systolic heart failure (New York Heart Association IV), incidence of sudden cardiac death decreases.27 The absolute rates of pump failure death and sudden cardiac death increases with decreasing left ventricular ejection fraction.28 However, it has been reported that the risk of sudden cardiac death is better correlated to left ventricular mass than to the ejection fraction.29 The left ventricular mass is increased considerably in both DHF and SHF; thus, the risk assessment for sudden cardiac death based on ejection fraction alone may not be appropriate. In a recent report, the risk of sudden cardiac death was found to be only 7% among 2314 patients, compared with death from other causes, which was 93%.30

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Fig. 1. One-year mortality morbidity in patients with severe systolic (open bar) and diastolic (closed bar) heart failure. Although the mortality morbidity rate in patients with preserved systolic function is lower than that of patients with reduced systolic function, the mortality rate in both groups with severe heart failure was high. (Published with permission of Dauterman KW, Go AS, Rowell R, Gebretsadik T, Gettner S, Massie BM. Congestive heart failure with preserved systolic function in a statewide sample of community hospitals. J Card Failure 2001;7:221e8.25)

Risk Factors

Older age, hypertension, diabetes, obesity, and coronary artery disease are risk factors for both DHF and SHF. Although DHF is more common in elderly females, diastolic dysfunction is more common in elderly males.31 In DHF, hypertension is a more common risk factor.12 However, a substantial proportion of patients with SHF have a history of hypertension. In SHF, ischemic heart disease is the most common etiology, but many patients with DHF have coronary artery disease. In decompensated heart failure, 63% of patients with systolic and 54% of patients with diastolic heart failure have coronary artery disease.32 Thus, for prevention, modication of the same risk factors should be employed in both DHF and SHF.
Remodeling

The distinctive features of remodeling in DHF and SHF are summarized in Table 1 and illustrated in Fig. 2.33,34 In SHF, the left ventricular cavity size is increased with an increase in both end-diastolic and end-systolic volumes,
Table 1. Morphologic and Functional Changes in Diastolic vs Systolic Heart Failure Parameters
Left ventricular cavity size Left ventricular mass Mass/cavity Wall thickness End-diastolic stress End-systolic stress End-diastolic volume End-systolic volume Ejection fraction Mechanical dyssynchrony Left ventricular shape and geometry

Diastolic Heart Failure

Normal or decreased Increased Increased Increased Increased Normal Normal Normal or decreased Normal May be present Usually remains unchanged

Systolic Heart Failure

Increased Increased Normal or decreased Decreased Increased Increased Increased Increased Decreased May be present Spherical

decreased or unchanged wall thickness, increased wall stress, and reduced ejection fraction. The mass is increased, but the mass/cavity ratio remains unchanged or is decreased. In SHF, there is an alteration in ventricular shape and geometry with a greater increase in transverse than in long axis, and mechanical dyssynchrony with or without electrical dyssynchrony occur in a substantial number of patients.35 In DHF, the cavity size remains unchanged or may even decrease, and the end-diastolic and end-systolic volumes remain normal or decrease. In DHF, there is usually an increase in wall thickness and mass; however, mass/cavity ratio is substantially increased. In DHF, enddiastolic wall stress is increased and systolic wall stress remains normal and ejection fraction remains normal or may even be higher than normal.9,34 In DHF, signicant alteration in ventricular shape and geometry is uncommon; however, mechanical dyssynchrony may occur even without electrical dyssynchrony.35,36 The left ventricular morphologic and functional changes in DHF and SHF compared to controls as evaluated by echocardiographic studies are summarized in Table 2.11 The differences in the structural changes in systolic and diastolic heart failure are summarized in Table 3 and illustrated in Fig. 3. In SHF there is myocyte lengthening and an increase in myocyte length/width ratio. The sarcomeres are replicated in parallel. In DHF there is an increase in the myocyte cross-sectional area with little or no change in its length/width ratio. The sarcomeres are replicated in parallel. The abnormality in calcium regulation occurs in both types of heart failure. Increased collagen volume and brosis occur in both but the character and degree of brosis appear to be different. In animal models, in SHF, there is degradation and disruption of brillar collagen; in contrast, in the pressure-overloaded hypertrophy which is associated with diastolic failure, there is an increase in collagen with increased width and continuity of the brillar collagen.34 The collagen cross links are decreased in SHF and increased in DHF. In general the matrix metalloproteinases

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Fig. 2. Ventricular remodeling in systolic and diastolic heart failure. (Left) Autopsy examples; (right) cross-sectional 2-dimensional echocardiographic views of systolic and diastolic heart failures compared with normals are illustrated. In systolic heart failure, the left ventricular cavity is markedly dilated and wall thickness is not increased. In diastolic heart failure, the cavity size is normal or decreased and wall thickness is markedly increased. (Reprinted with permission.33)

are increased in SHF and decreased in DHF. In contrast, their endogenous tissue inhibitors tend to decrease in SHF and increase in DHF.37,38 Other biochemical evidences for abnormal collagen metabolism such as increased circulating levels of amino-terminal propeptide of Type III procollagen have been reported in systolic heart failure.39 The titin isoforms N2BA/N2B ratio is decreased in systolic failure and it is increased in diastolic failure.2 Left ventricular endomyocardial biopsy studies have reported an increase in myocyte diameter and less decrease in myocyte volume in

Table 2. Echocardiographic Left Ventricular Morphologic and Functional Characteristics in Primary Systolic and Diastolic Heart Failure Compared With Controls Controls
LVEDV (mL) 102 6 12 LVESV (mL) 46 6 11 LVEF % 54 6 2 LV mass (g) 125 6 12 LV mass/ 1.49 6 0.17 volume NE pg/mL 169 BNP pg/mL 3

DHF compared with SHF, whereas collagen volume fractions increased in both types.40 The initiating stimuli for remodeling in SHF and DHF have not been clearly delineated. In SHF, after acute myocardial infarction, the extent of myocardial injury and the magnitude of left ventricular systolic dysfunction appear to be the major determinants. A small infarct and relatively preserved ejection fraction is not usually associated with ventricular remodeling.41,42 Abnormal neurohormonal activation has also been implicated as a major mechanism for progressive remodeling in systolic heart failure.43 In DHF, the stimuli for ventricular remodeling remain unclear. The pressure overload resulting from hypertension

Systolic Heart Failure

192 137 31 232 1.22 6 6 6 6 6 10* 9* 2* 9* 0.14

Diastolic Heart Failure

87 37 60 160 2.12 6 6 6 6 6 10 9 2y 9y 0.14z

Table 3. Diastolic and Systolic Heart Failure Remodeling: Myocyte and Matrix Changes Systolic Heart Failure
Myocyte Hypertrophy Apoptosis Necrosis Myocardial brosis Calcium regulation MMPs/TIMPs Collagen cross-links Titin isoforms N2BA/ N2B e e e

Diastolic Heart Failure

e e

287 28

306; P 5 .007 56; P 5 .02

Adapted from Kitzman DW, et al. JAMA 2002;288:2144e50.11 LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume; LVEF, left ventricular ejection fraction; LV, left ventricle; NE, norepinephrine; BNP, B-type natriuretic peptide. *Systolic heart failure vs. controls, P ! .001. y Diastolic heart failure vs. controls, P ! .001. z Diastolic heart failure vs. controls, P ! .002.

, increased; e, decreased or impaired; MMPs, matrix metalloproteinases; TIMPs, tissue inhibitors of metalloproteinases.

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Fig. 3. Changes in myocytes (left) and in extracellular matrix (right) in systolic heart failure resulting from dilated cardiomyopathy, and diastolic heart failure resulting from pressure over load compared with normals in animal models. In systolic heart failure, the myocyte length is increased without any change in the cross-sectional area; in diastolic heart failure, the cross-sectional area of the myocyte is increased without a signicant change in its length. In systolic heart failure, collagen degradation and disruption occur; in diastolic heart failure, there is increased width and continuity of brillar collagen. (Reprinted with permission.34)

and obesity associated with concentric hypertrophy is likely to be an important contributing factor. Neurohormonal abnormalities, similar to those observed in systolic heart failure, occur in DHF.11 Thus neurohormonal abnormalities do not explain differences in ventricular remodeling in DHF and SHF. It is possible that neurohormonal abnormalities produce different substrate response in DHF and SHF.
Functional Changes

In SHF, impaired contractile function is the principal functional derangement and is the major mechanism for reduced ejection fraction (Fig. 3).34,44 The other mechanism

for reduced ejection fraction in SHF is increased wall stress. Diastolic function, as assessed by echo-Doppler studies, is frequently abnormal in patients with overt SHF. Impaired left ventricular relaxation and increased passive stiffness is the principal functional derangement in DHF.34 The pressure-volume relation during diastole shifts upward and to the left (Fig. 4); as a result there is a disproportionately greater increase in diastolic pressure for any increase in volume.45 The hemodynamic prole may be similar in SHF and DHF. In SHF, reduced ejection fraction results in a decrease in stroke volume and cardiac output. Increased left ventricular end-diastolic volumes and often associated abnormal

Fig. 4. Schematic diagram of pressure-volume relations in normals, systolic and diastolic heart failure. In systolic heart failure, a downward and rightward shift of the end-systolic pressure-volume line indicates decreased contractile function, which is the principal cause of reduced ejection fraction and forward stroke volume. In primary diastolic heart failure, diastolic pressure-volume relation (dashed line) shifts upward and to the left, indicating a disproportionate and a greater increase in diastolic pressure for any increase in diastolic volumes. If there is also a decrease in end-diastolic volume, then a decrease in stroke volume also occurs. (Reprinted with permission.44)

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Fig. 5. The changes in the diastolic pressure-volume relation in patients with overt diastolic heart failure, illustrating its shifts upward and to the left. (Reprinted with permission.45)

diastolic lling result in increased left ventricular diastolic pressure, a passive increase in left atrial and pulmonary venous pressure, and postcapillary pulmonary arterial hypertension. Right ventricular failure and systemic venous hypertension and its hemodynamic and clinical consequences occur. In DHF, because of the disproportionate increase in left ventricular diastolic pressure, there is an increase in left atrial and pulmonary venous pressure that is associated with symptoms and signs of pulmonary venous congestion (Fig. 5).45 Postcapillary pulmonary hypertension resulting from increased pulmonary venous pressure may precipitate right heart failure. Left ventricular stroke volume and cardiac output may also decline because of decreased enddiastolic volume (preload dependent). Chronic elevation of pulmonary venous pressure may be associated with increased pulmonary vascular resistance from secondary pulmonary vasoconstriction, which may occur in both SHF and DHF.
Does Left Ventricle Dilate in Diastolic Heart Failure?

ejection fraction remain unchanged, but end-diastolic pressure and stiffness index increase, suggesting that in DHF ventricular dilatation does not occur and worsening diastolic function is the mechanism for development and progression of heart failure (Table 4).46,47 Thus left ventricle size remains unchanged and it does not dilate without an ischemic insult.
Differences in Therapeutic Options

Left ventricular dilation always occurs in SHF. In DHF, however, left ventricular dilation does not appear to occur without an additional insult such as myocardial infarction. In some patients with DHF without coronary artery disease, serial assessment of ventricular volumes and pressures and stiffness have been performed; end-diastolic volumes and

Although there have been considerable advances in the treatment of SHF, very little progress has been made in the management of DHF. The improvement in prognosis in SHF is most likely related to the therapeutic discoveries that have been observed to attenuate adverse remodeling and improve hemodynamic abnormalities. The neurohormonal modulators such as renin-angiotensin-aldosterone and adrenergic antagonists clearly improve symptoms and quality of life and decrease mortality. So far no such therapies have been discovered for improving prognosis in patients with DHF. Angiotensin receptor blocking agents have the potential for decreasing morbidity but not mortality.24 It has been reported that statin therapy has the potential to decrease mortality of patients with DHF.48 Statin therapy is also associated with lower mortality in SHF.49 Chronic resynchronization therapy with or without implantable cardioverter debrillator improves prognosis of patients with SHF. However, chronic resynchronization therapy has not been shown to produce benecial effects in DHF. Cardiac transplantation is likely to benet selected patients either with SHF or DHF. Conclusion Established clinical systolic and diastolic heart failure appear to be 2 distinct syndromes of chronic heart failure. The myocardial structural and primary functional derangements are distinctive in these 2 syndromes, although hemodynamic consequences, clinical presentations, signs and symptoms, and prognosis are similar. The neurohormonal abnormalities are also similar in both of these syndromes. Although there have been considerable advances in the

Table 4. Changes in Left Ventricular End Diastolic Volumes (LVEDVI) and Pressures (LVEDP), Ejection Fraction (LVEF), and Left Ventricular Stiffness Modulus (Stiff-Mod) During 64 6 9 Months in Patients With DHF Initial
LVEDVI mL/m2 LVEF % LVEDP mm Hg Stiff-Mod kN/m2 68 67 14 3.4 6 6 6 6 9 3 3 0.6

End of Follow-up
76 60 26 6.3 6 6 6 6 8 4 2* 0.9*

Published with permission.46 *P ! .05 follow-up vs. initial.

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management of systolic heart failure, the management of DHF remains primarily to relieve symptoms. Because of inadequate knowledge of the molecular and biochemical mechanisms of the structural remodeling and principal functional derangement in diastolic heart failure, treatments to improve prognosis have not evolved. Thus further basic science and clinical research is urgently required. However, potential exists for discovery of therapeutic agents to improve fundamental abnormalities of the cytoskeleton and myocardial architecture and thereby decrease myocardial stiffnessdthe principal functional derangement in diastolic heart failure. Until then the treatment of diastolic heart failure will remain empirical.

17.

18.

19.

20.

Acknowledgment The authors are grateful to Marci Yellin for her invaluable assistance in preparing the manuscript.

21.

22.

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