© 2007 European Society of Cardiology
Systolic and diastolic heart failure: Different phenotypes of the same disease?
Department of Physiology, University of Antwerp, Antwerp, Belgium and Division of Cardiology, Middelheim Hospital Groenenborgerlaan 171, 2020 Antwerpen, Belgium
* Corresponding author. Tel.: +32 3 2653 277; fax: +32 3 2653 276. E-mail address: gilles.dekeulenaer{at}ua.ac.be
 |
Abstract |
|---|
 Top Abstract 1. Introduction2. Need to adjust...3. Diastolic heart failure...4. Conclusion: systolic and...References |
|---|
Traditional pathophysiological concepts of chronic heart failure have largely focused on the haemodynamic consequences of ventricular systolic dysfunction. How these concepts relate to the pathophysiology of diastolic heart failure, i.e., heart failure with a preserved ejection fraction is, however, unclear, causing uncertainty about pathophysiology, diagnosis and management.
Recent measurements of regional myocardial systolic function in patients with diastolic heart failure indicate that systolic and diastolic heart failure may be more closely related than previously anticipated. Rather than being considered as separate diseases with a distinct pathophysiology, systolic and diastolic heart failure may be merely different clinical presentations within a phenotypic spectrum of one and the same disease. In this review, we will interpret these new insights in a broader conceptual context of chronic heart failure and design novel paradigms in which systolic and diastolic heart failure jointly progress in a pathophysiological time trajectory of only one disease.
Key Words: Chronic heart failure • Diastole • Relaxation • Ventricular function
Received October 26, 2005; Revised February 20, 2006; Accepted May 24, 2006
|
1. Introduction |
|---|
|
TopAbstract1. Introduction2. Need to adjust...3. Diastolic heart failure...4. Conclusion: systolic and...References |
|---|
Epidemiological studies have established that the incidence of chronic heart failure is increasing [1,2]. These studies have also revealed that about half of the patients with chronic heart failure have a normal left ventricular ejection fraction (>50%). Although originally viewed as a mild disease, it now appears that heart failure at a preserved ejection fraction (HFprEF) leads to an increased annual mortality of 5-8% (compared with 10-15% for patients with systolic heart failure). [3-5] In patients over 70 years old, the mortality rates for HfprEF and heart failure at reduced ejection fraction may be nearly equal. With respect to morbidity, the impact of HFprEF is high with readmission rates being similar to heart failure at reduced ejection fraction (6-month all-cause readmission rate 45%) [6,7], reflecting the episodic clinical course of the disease with sudden exacerbations triggered by atrial fibrillation, hypertension, infections, medical non-compliance, etc. [8].
Despite these observations, consensus on the definition and diagnostic criteria of this syndrome is still missing [9-12]. The syndrome is randomly called "heart failure with preserved ejection fraction" or "diastolic heart failure", or-erroneously as we will see later-"heart failure with preserved systolic function". Traditional concepts and clinical trial design in chronic heart failure have largely focused on the haemodynamic consequences of heart failure with a reduced ejection fraction ("systolic heart failure"), leaving HFprEF as a "separate" disease with no consensus on the pathophysiology and without proven therapy.
Yet, how strong is the evidence that the mechanical pump abnormalities observed in HFprEF (ventricular relaxation disturbances and increased ventricular stiffness [13]) develop independently from the (mal)adaptive forces in systolic heart failure? Alternatively, is there enough evidence to counter the hypothesis that the pathophysiology of HFprEF is essentially identical, or at least strongly related, to the pathophysiology of systolic heart failure?
|
2. Need to adjust diagnostic criteria to new pathophysiological insights |
|---|
|
TopAbstract1. Introduction2. Need to adjust...3. Diastolic heart failure...4. Conclusion: systolic and...References |
|---|
Despite numerous attempts to develop diagnostic criteria for HFprEF, diagnostic guidelines have remained unsatisfactory [14,15]. Critiques have been formulated towards the overemphasis on the presence of diastolic abnormalities on the one hand, and on the shortcomings of using ejection fraction as a parameter of systolic function. First, although impaired relaxation and genuine diastolic abnormalities undoubtedly contribute to symptoms and in fact are found in all patients with HFprEF [16], a slow left ventricular relaxation pattern is observed in many individuals without symptoms or signs of heart failure. Hence, there is clearly a need to include supplementary factors-i.e., "disease modifiers" as we will see below-that may influence the clinical impact of impaired relaxation.
Second, ejection fraction is a convenient measure of overall haemodynamic pump dysfunction, but a poor measure of systolic muscular pump dysfunction. Recent studies on the mechanical ventricular properties in patients diagnosed with HFprEF have consistently revealed abnormalities of left ventricular systolic function. For example, performance of longitudinal myocardial fibers has been measured by long-axis M mode echo or tissue Doppler imaging (TDI) in patients with HFprEF. These measurements revealed depressed contractile performance in patients with HFprEF and in patients with asymptomatic diastolic dysfunction, despite a preserved ejection fraction [17-26] (Fig. 1).
|
These observations, therefore, support the hypothesis that HFprEF and systolic heart failure may be more closely related than previously anticipated. In other words, the conjecture that HFprEF is a distinct disease in which systolic myocardial function is preserved seems at least inaccurate. HFprEF should, instead, be regarded as a variant form of systolic heart failure, but in which symptoms and signs develop prematurely. Although several investigators have formulated this view previously [17-26], it nevertheless still remains controversial, in part due to attempts by some to re-define terms of cardiac performance. In our opinion, these attempts have favoured existing uncertainties and misunderstandings [27]. We will, therefore, briefly summarize these misunderstandings, and explain how they should be re-interpreted to become consistent with the insights reviewed in this paper.
Misunderstanding 1: "Analysis of ventricular performance in HFprEF does not show systolic abnormalities."
It has been recently established [27,28] that parameters of global systolic performance of the left ventricle on cardiac catheterization (stroke work, preload recruitable stroke work, ejection fraction, systolic stress-shortening relationship, end-systolic pressure-volume relationship, and peak (+)dP/dt) in patients with HFprEF were not different from control patients and that only parameters of left ventricular relaxation and diastolic stiffness were impaired. From these observations, the investigators concluded that the "pathophysiology of HFprEF does not appear to be related to significant abnormalities in the systolic properties of the left ventricle".
Above-mentioned conclusions seem reasonable enough, as long as one views the heart as a mere haemodynamic pump as historically proposed by Wiggers [29], Rushmer [30] and Sarnoff [31]. From the observations by Abbott and Mommaerts [32] and Sonnenblick [33], it became clear, however, that any evaluation of cardiac performance ought to include, in addition, some properties of cardiac muscle. If perceived as a mere haemodynamic [26,27], rather than as a muscular pump, the above measurements are, therefore, at least incomplete.
From the perception of a traditional haemodynamic pump, preservation of peripheral perfusion pressure, stroke volume, and cardiac output (blood flow)-as well as all related or derived parameters, such as, e.g., stroke work, pressure-volume and stress-shortening relations, +dP/dt and other derivatives-is of key importance. In normal conditions, the higher end-diastolic volume, the higher is stroke volume, the ratio of stroke volume-to-end-diastolic volume being calculated as the ejection fraction, which remains constant. Under stress (e.g., after an acute myocardial infarction), the heart is able to maintain stroke volume, as well as peripheral flow and perfusion pressure; hence, haemodynamic pump performance, constant for some time, but only at the expense of an inappropriately increased end-diastolic volume with concomitant ventricular remodelling. The ensuing progressive decline in calculated ejection fraction must, therefore, be seen as an early sensitive sign of this inappropriately increased end-diastolic volume and remodelling, and hence, of haemodynamic pump failure.
Regional and temporal contractile properties of ventricular cardiac muscle are, however, most often impaired at a much earlier stage. Hence, consistent with recent echo-Doppler analysis [17-25]-particularly in hearts with concentric hypertrophy that are hampered somehow to increase their end-diastolic volume-substantial systolic dysfunction at rest and during adrenergic stimulation [34] may be present already when mean overall haemodynamic pump performance, including its most sensitive mechanical index ejection fraction, is still well preserved. In addition to myocardial temporal and regional non-uniformities, this early stage of systolic dysfunction is also characterized by significant left ventricular relaxation abnormalities, i.e., in rate and time of onset. Importantly, in a muscular-unlike a haemodynamic-pump, ventricular relaxation should be regarded as an intrinsic part of systole. Moreover, as the haemodynamic pump index ejection fraction is blind for such early changes in cardiac muscular pump performance, it is too insensitive, hence inappropriate, to characterize a group of patients with symptoms of heart failure resulting from such abnormalities, i.e., diastolic heart failure, as being distinct from other patients with chronic heart failure. A fortiori, therefore, measurements advocated by some [27,28] of haemodynamic pump performance-some of which being less sensitive still than ejection fraction-can hardly provide a sufficiently solid argument to conclude that the "pathophysiology of HFprEF does not appear to be related to significant abnormalities in the systolic properties of the left ventricle."
Misunderstanding 2: "HFprEF does not fit within current pathophysiological paradigms of chronic heart failure".
In a traditional conceptual view on the pathophysiology of chronic heart failure, cardiac function is regarded as evolving within a vicious circle of (de)compensatory mechanisms, gradually and irreversibly spiralling down until end-stage pump failure, or until death ensues prematurely. This pathophysiological model is most suitable to illustrate the complementary contribution of the underlying systemic (mal)adaptative reactions, i.e., haemodynamic overload, neurohormonal activation, enhanced pro-inflammatory cytokine activity and endothelial dysfunction [35]. A disadvantage of this model is, however, that it lacks a time dimension, thereby neglecting the time-dependent evolution of symptom severity. In clinical practice, the symptoms in many patients, especially those with HFprEF, evolve clearly out of phase with the pathophysiological progression of overall pump dysfunction. As this important paradox of chronic heart failure remains unappreciated, HFprEF does not seem to fit within the above traditional paradigm of chronic heart failure. In the following paragraphs, we will, therefore, review two alternative paradigms of chronic heart failure and investigate how their pathophysiology relates to HFprEF.
|
3. Diastolic heart failure and alternative paradigms of chronic heart failure |
|---|
|
TopAbstract1. Introduction2. Need to adjust...3. Diastolic heart failure...4. Conclusion: systolic and...References |
|---|
3.1. A time-dependent progression model of chronic heart failure
In a time-dependent model of chronic heart failure, depicted in Fig. 2 as a time trajectory of cardiac pump performance, the progression of chronic heart failure can be subdivided in three consecutive pathophysiological stages.
|
Under stress, the heart recruits various compensatory autoregulatory mechanisms. A fundamental feature of this first and very early "systolic activation" or pre-disease stage is the capacity of the heart to delay the onset of ventricular relaxation. This often ignored or underestimated feature allows the ventricle to modulate systolic time duration during which a given amount of stroke work is delivered [36-38]. In a second stage ("mild systolic dysfunction"), as commonly observed during the initial phases of myocardial hypertrophy and ischemia, the above autoregulatory mechanisms become maladaptive. Typically, ventricular relaxation either regionally or globally becomes abnormally slow and impaired with a progressive loss of the ventricle to modulate the timing of onset of relaxation. It can be commonly detected as an abnormal mitral inflow signal during Doppler echocardiography (E/A inversion). Impaired relaxation is caused by three major processes, including (i) dysfunction of intracellular myocardial inactivation processes, (ii) inappropriate loading—including those induced by arterial elastance abnormalities and (iii) excessive non-uniformity [36-39]. Besides relaxation disturbances, the systolic function abnormalities of the ventricular muscular pump can be objectified by TDI, by abnormal systolic time intervals and by increased BNP levels [24]. During this second "mild systolic dysfunction" stage, haemodynamic pump performance, as reflected by the ejection fraction (>50%) is well preserved thanks to a well-compensated performance of the ventricular haemodynamic pump.
Finally during a third stage ("pump failure"), deteriorating haemodynamic pump performance may reach a critical threshold as evident from an ejection fraction below 40-45% with severe systolic and diastolic abnormalities. Meanwhile, hypertrophy of the ventricle irreversibly evolves into so-called adverse remodelling. Adverse remodelling is still an ill-defined term indicating the presence of a number of structural and functional abnormalities, which may result in myocardial fibrosis/necrosis and irreversible dilatation.
An advantage of this model is that the time progression of the clinical symptoms of chronic heart failure can be superimposed on the time trajectory of the above pathophysiological progression. In chronic heart failure, it is silently assumed as if the severity of clinical symptoms develops uniformly in all patients and synchronously with the severity of pump failure, in which NYHA class IV symptoms occur at ejection fractions below 20% (e.g., patient A in Fig. 2 lower). The latter presentation does not, however, comply with daily clinical practice and with the observation that left ventricular ejection fraction correlates poorly with exercise tolerance. Indeed, a large proportion of heart failure patients in NYHA class III and IV may already be diagnosed clinically at an earlier pathophysiological stage of pump failure, e.g., with ejection fractions clearly above 30-40% (e.g., patient B in Fig. 2 lower) or even above 45-50%, indicating that overall pump performance is preserved. Importantly, as indicated above, in the latter patients systolic abnormalities, including significant myocardial contraction-relaxation non-uniformities and impaired relaxation can be detected (e.g., patient C in Fig. 2 lower). The latter group corresponds to patients with so-called HFprEF, and sometimes denoted-erroneously-as heart failure with preserved systolic function.
Hence, superimposing symptom progression and pathophysiological progression in a time-progression model of chronic heart failure allows incorporation of HFprEF and systolic heart failure within one and the same pathophysiological time trajectory, in which the two types of heart failure only differ in the onset of their clinical manifestation, but not in the presence or absence of systolic abnormalities. In terms of chronological stages of disease, HFprEF comes earlier than systolic heart failure, suggesting that HFprEF could perhaps progress into systolic heart failure. Consistently, in a recent survey in predominantly hypertensive African-American patients with LV hypertrophy and a normal ejection fraction (EF), 18% developed a reduced EF after a median follow-up of approximately 4 years, with a markedly increased risk for this outcome when pulmonary oedema was seen on a chest X-ray [40]. Similarly, in about 20% of patients hospitalised for acute heart failure and a preserved ejection fraction, the ejection fraction was <45% during a follow-up visit 3 months later, this in absence of intermediate acute coronary complications [41].
3.2. A phenotype model of chronic heart failure
In this model shown in Fig. 3, chronic heart failure is, again, presented as one disease but with multiple patient-specific diverging phenotypical trajectories. Each patient follows his/her own distinct individual time trajectory of progressively deteriorating pump performance, the trajectory depending on a number of disease modifiers. In a large group of heart failure patients, a wide spectrum of different phenotypes can thus be identified, with two extreme presentations at each end of the spectrum. On the far left, patients suffer from primary diastolic dysfunction; at end stage, these patients have non-dilated ventricles, normal or high ejection fraction, high filling pressures and NYHA class IV symptoms but no signs of even mild global or regional systolic dysfunction, a disease that is probably non-existent. On the far right, patients develop NYHA class IV symptoms at a stage when diastolic function is normal and only contractile dysfunction is apparent, a disease that is also probably non-existent. An important recent study by Yotti et al. [42] suggests that in patients with dilated cardiomyopathy, ventricular dilatation itself impairs diastolic filling by enhancing convective deceleration; along with a slowed relaxation, reduced elastic recoil, and displacement onto the stiff portion of the passive pressure-volume relation, increased convective deceleration may thus contribute to diastolic dysfunction in the patients.
|
Accordingly, most if not all cases of heart failure (e.g., patients A, B and C of Fig. 3), are hybrids within this spectrum with combined systolic and diastolic abnormalities and with symptoms developing at normal, slightly reduced, moderately reduced or severely reduced left ventricular ejection fraction, the latter being an index of global haemodynamic pump performance, rather than of systolic function. The direction of the patient's trajectory towards a heart failure phenotype with either preserved or reduced ejection fraction depends, in our opinion, on a number of disease modifiers in which genetic, molecular, environmental and phenotypical factors may interact.
Comparing clinical characteristics of heart failure patients with either preserved or reduced ejection fraction can easily identify a number of important modifier candidates. In Fig. 3 (lower), for example, gender, incidence of hypertension and of diabetes have been compared for three different groups of heart failure patients, i.e., with normal (>50%), slightly reduced (>40%) or markedly impaired (<40%) ejection fractions, respectively [43-45]. Strikingly, female gender, diabetes and hypertension were much more common in the first group compared with the last group, and at intermediate incidence in the second group. Based on these observations, it is attractive to speculate that in each individual patient, a set of disease modifiers (which probably also include age, myocardial hypertrophy, physical fitness, cholesterol levels, etc.) will influence the phenotypical trajectory of heart failure. In other words, after a cardiac insult, disease modifiers may direct the disease towards a predominantly "systolic" or "diastolic" heart failure phenotype. If the modifier directs towards diastolic heart failure, it will somehow prevent ventricular remodelling and dilatation of systolic heart failure, and perhaps to some extent prognosis. This phenomenon has been demonstrated for diabetes, obesity, hypertension and hypercholesterolemia [46-50].
Explaining underlying mechanisms through which disease modifiers affect the clinical course of heart failure is a difficult challenge and a subject of ongoing research. Each of the modifiers may influence or be influenced by systemic physiological pathways (e.g., neurohormonal activity, endothelial function, etc.), cardiac molecular properties (levels of gene expression, post-translational modifications) and genotypic characteristics (gene deletions, gene polymorphisms, etc). Females with myocardial injury/overload, for example, express a sex-specific cluster of myocardial genes during disease progression [51], whereas gene deletions differently affect progression of heart failure in females and males [52-54].
An interesting aspect in this discussion may be the link between disease modifiers and cardiac molecular mechanisms that determine ventricular relaxation and stiffness as the latter processes determine diastolic function, left ventricular end-diastolic pressures and symptoms of heart failure [55-57]. As previously shown [58-60], diastolic function is a target for modification by most if not all of the mentioned disease modifiers, including gender, diabetes, obesity, sedentary life style, myocardial hypertrophy and hypertension. In a study by Fischer et al. [58] in the absence of these modifiers, diastolic abnormalities were rare (4.3% vs 11.1%) in the general population, even in the elderly. Importantly, and consistent with the present hypothesis, diastolic dysfunction recovered upon corrections of these modifiers, at least for obesity [59] and sedentary lifestyle [60]. Furthermore, further down on a sub-cellular scale, a direct molecular link (e.g., titin isoform expression, SERCA-2a gene expression, abnormalities in high energy phosphate metabolism and secondary impaired calcium sequestration and matrix metalloproteinase activity) between the modifier and diastolic dysfunction has been demonstrated for some conditions, including age [61,62], hypertension [63,64] and diabetes [65].
|
4. Conclusion: systolic and diastolic heart failure; different phenotypes of the same disease |
|---|
|
TopAbstract1. Introduction2. Need to adjust...3. Diastolic heart failure...4. Conclusion: systolic and...References |
|---|
In the present review, we have discussed arguments endorsing the hypothesis that HFprEF is a variant form of systolic heart failure in which symptoms develop prematurely. Central to this discussion were considerations about the heart as a muscular pump in which-unlike a mere haemodynamic pump-the mechanical performance of the heart was interpreted in terms of cardiac muscle as well as cardiac pump parameters. Next, re-introducing time dimensions in the disease progression model allowed the incorporation of the pathophysiological as well as the clinical manifestation of HFprEF within an overall pathophysiological time trajectory of chronic heart failure. We hypothesize, therefore, that from a pathophysiological point of view systolic and HFprEF progress along a single pathophysiological time trajectory. From a clinical point of view, however, heart failure may progress along an infinite number of time trajectories dependent on a complex interaction of disease modifiers unique for each individual patient. Accordingly, patients may develop signs and symptoms of heart failure over a wide range of pathophysiological stages of the same disease, varying from stages with mild systolic impairment (and a preserved ejection fraction) to stages with severely depressed systolic function (and severely reduced ejection fraction), leading to a continuous spectrum of heart failure phenotypes. By examining heart failure from this phenotype-oriented view, disease modifiers and their underlying mechanisms should be explored more carefully in clinical trials as they may reveal crucial aspects and individualized therapeutic targets of chronic heart failure. Clinicians should be conscious of these ongoing developments prior to undertaking initiatives for clinical trials and diagnostic as well as therapeutic guidelines. In the mean time, therapy to improve prognosis of HFprEF remains empirical and is essentially the same as for systolic heart failure, as both diseases seem to be part of the same disease process.
|
References |
|---|
|
TopAbstract1. Introduction2. Need to adjust...3. Diastolic heart failure...4. Conclusion: systolic and...References |
|---|
- Cleland J.G., Cohen-Solal A., Aguilar J.C., et al. Management of heart failure in primary care (the IMPROVEMENT of Heart Failure Programme): an international survey. Lancet (2002) 360:1631–1639.[CrossRef][Web of Science][Medline]
- Hogg K., Swedberg K., McMurray J. Heart failure with preserved left ventricular systolic function; epidemiology, clinical characteristics, and prognosis. J Am Coll Cardiol (2004) 43:317–327.
[Abstract/Free Full Text] - Setaro J.F., Soufer R., Remetz M.S., Perlmutter R.A., Zaret B.L. Long-term outcome in patients with congestive heart failure and intact systolic left ventricular performance. Am J Cardiol (1992) 69:1212–1216.[CrossRef][Web of Science][Medline]
- Judge K.W., Pawitan Y., Caldwell J., Gersh B.J., Kennedy J.W. Congestive heart failure symptoms in patients with preserved left ventricular systolic function: analysis of the CASS registry. J Am Coll Cardiol (1991) 18:377–382.[Abstract]
- Brogan W.C. III, Hillis L.D., Flores E.D., Lange R.A. The natural history of isolated left ventricular diastolic dysfunction. Am J Med (1992) 92:627–630.[CrossRef][Web of Science][Medline]
- Vasan R.S., Larson M.G., Benjamin E.J., Evans J.C., Reiss C.K., Levy D. Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: prevalence and mortality in a population-based cohort. J Am Coll Cardiol (1999) 33:1948–1955.
[Abstract/Free Full Text] - Aurigemma G.P., Gottdiener J.S., Shemanski L., Gardin J., Kitzman D. Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: the cardiovascular health study. J Am Coll Cardiol (2001) 37(4):1042–1048.
[Abstract/Free Full Text] - Banerjee P., Clark A.L., Nikitin N., Cleland J.G. Diastolic heart failure. Paroxysmal or chronic? Eur J Heart Fail (2004) 6:427–431.
[Abstract/Free Full Text] - Thomas M.D., Fox K.F., Coats A.J., Sutton G.C. The epidemiological enigma of heart failure with preserved systolic function. Eur J Heart Fail (2004) 6:125–136.
[Abstract/Free Full Text] - Burkhoff D., Maurer M.S., Packer M. Heart failure with a normal ejection fraction: is it really a disorder of diastolic function? Circulation (2003) 107:656–658.
[Free Full Text] - Maurer M.S., Spevack D., Burkhoff D., Kronzon I. Diastolic dysfunction: can it be diagnosed by Doppler echocardiography? J Am Coll Cardiol (2004) 44:1543–1549.
[Abstract/Free Full Text] - Hogg K., McMurray J. Neurohumoral pathways in heart failure with preserved systolic function. Prog Cardiovasc Dis (2005) 47:357–366.[CrossRef][Web of Science][Medline]
- Zile M.R., Baicu C.F., Gaasch W.H. Diastolic heart failure-abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med (2004) 350:1953–1959.
[Abstract/Free Full Text] - European Study Group on Diastolic Heart Failure. How to diagnose diastolic heart failure. Eur Heart J (1998) 19:990–1003.
[Free Full Text] - Vasan R.S., Levy D. Defining diastolic heart failure: a call for standardized diagnostic criteria. Circulation (2000) 101:2118–2121.
[Free Full Text] - Zile M.R., Gaasch W.H., Carroll J.D., et al. Heart failure with a normal ejection fraction: is measurement of diastolic function necessary to make the diagnosis of diastolic heart failure? Circulation (2001) 104:779–782.
[Abstract/Free Full Text] - Yu C.M., Lin H., Yang H., Kong S.L., Zhang Q., Lee S.W. Progression of systolic abnormalities in patients with "isolated" diastolic heart failure and diastolic dysfunction. Circulation (2002) 105:1195–1201.
[Abstract/Free Full Text] - Yip G., Wang M., Zhang Y., Fung J.W., Ho P.Y., Sanderson J.E. Left ventricular long axis function in diastolic heart failure is reduced in both diastole and systole: time for a redefinition? Heart (2002) 87:121–125.
[Abstract/Free Full Text] - Bruch C., Gradaus R., Gunia S., Breithardt G., Wichter T. Doppler tissue analysis of mitral annular velocities: evidence for systolic abnormalities in patients with diastolic heart failure. J Am Soc Echocardiogr (2003) 16:1031–1036.[CrossRef][Web of Science][Medline]
- Sanderson J.E. Diastolic heart failure: fact or fiction? Heart (2003) 89:1281–1282.
[Free Full Text] - Petrie M.C., Caruana L., Berry C., McMurray J.J. "Diastolic heart failure" or heart failure caused by subtle left ventricular systolic dysfunction. Heart (2002) 87:29–31.
[Abstract/Free Full Text] - Nikitin N.P., Witte K.K., Clark A.L., Cleland J.G. Color tissue Doppler-derived long-axis left ventricular function in heart failure with preserved global systolic function. Am J Cardiol (2002) 90:1174–1177.[CrossRef][Web of Science][Medline]
- Vinereanu D., Nicolaides E., Tweddel A.C., Fraser A.G. "Pure" diastolic dysfunction is associated with long-axis systolic dysfunction. Implications for the diagnosis and classification of heart failure. Eur J Heart Fail (2005) 7:820–828.
[Abstract/Free Full Text] - Vinereanu D., Lim P.O., Frenneaux M.P., Fraser A.G. Reduced myocardial velocities of left ventricular long-axis contraction identify both systolic and diastolic heart failure—a comparison with brain natriuretic peptide. Eur J Heart Fail (2005) 7:512–519.
[Abstract/Free Full Text] - Hasegawa H., Little W.C., Ohno M., et al. Diastolic mitral annular velocity during the development of heart failure. J Am Coll Cardiol (2003) 41:1590–1597.
[Abstract/Free Full Text] - Brutsaert D.L., De Keulenaer G.W. Diastolic heart failure: a myth. Curr Opin Cardiol (2006) 21:240–248.[Web of Science][Medline]
- Aurigemma G.P., Zile M.R., Gaasch W.H. Contractile behavior of the left ventricle in diastolic heart failure: with emphasis on regional systolic function. Circulation (2006) 113(2):296–304.
[Free Full Text] - Baicu C.F., Zile M.R., Aurigemma G.P., Gaasch W.H. Left ventricular systolic performance, function, and contractility in patients with diastolic heart failure. Circulation (2005) 111:2306–2312.
[Abstract/Free Full Text] - Wiggers C.J. Determinants of cardiac performance. Circulation (1951) 4:485–495.[Abstract]
- Rushmer R.F. Anatomy and physiology of ventricular function. Physiol Rev (1956 (Jul.)) 36:400–425.
[Free Full Text] - Sarnoff S.J. Related Myocardial contractility as described by ventricular function curves; observations on Starling's law of the heart. Physiol Rev (1955) 35:107–122.
[Free Full Text] - Abott B.C., Mommaerts W.F. A study of inotropic mechanisms in the papillary muscle preparation. J Gen Physiol (1959) 42:533–551.
[Abstract/Free Full Text] - Sonnenblick E.H. Force-velocity relations in mammalian heart muscle. Am J Physiol (1962) 202:931–939.
[Abstract/Free Full Text] - Kozakova M., Fraser A.G., Buralli S., et al. Reduced left ventricular functional reserve in hypertensive patients with preserved function at rest. Hypertension (2005) 45(4):619–624.
[Abstract/Free Full Text] - Brutsaert D.L. Cardiac endothelial-myocardial signaling: its role in cardiac growth, contractile performance, and rhythmicity. Physiol Rev (2003) 83:59–115.
[Abstract/Free Full Text] - Brutsaert D.L., Sys S.U. Diastolic dysfunction in heart failure. J Card Fail (1997) 3:225–242.[CrossRef][Medline]
- Brutsaert D.L., Sys S.U. Relaxation and diastole of the heart. Physiol Rev (1989) 69:1228–1315.
[Abstract/Free Full Text] - Brutsaert D.L., Rademakers F.E., Sys S.U. Triple control of relaxation: implications in cardiac disease. Circulation (1984) 69:190–196.
[Free Full Text] - Kawaguchi M., Hay I., Fetics B., Kass D.A. Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: implications for systolic and diastolic reserve limitations. Circulation (2003) 107:714–720.
[Abstract/Free Full Text] - Rame J.E., Ramilo M., Spencer N., et al. Development of a depressed left ventricular ejection fraction in patients with left ventricular hypertrophy and a normal ejection fraction. Am J Cardiol (2004) 93:234–237.[CrossRef][Web of Science][Medline]
- Cahill J.M., Ryan E., Travers B., Ryder M., Ledwidge M., McDonald K. Progression of preserved systolic function heart failure to systolic dysfunction—a natural history study. Int J Cardiol (2006) 106:95–102.[CrossRef][Web of Science][Medline]
- Yotti R., Bermejo J., Antoranz J.C., et al. A noninvasive method for assessing impaired diastolic suction in patients with dilated cardiomyopathy. Circulation (2005) 112:2921–2929.
[Abstract/Free Full Text] - Klapholz M., Maurer M., Lowe A.M., et al. Hospitalization for heart failure in the presence of a normal left ventricular ejection fraction: results of the New York Heart Failure Registry. J Am Coll Cardiol (2004) 43:1432–1438.
[Abstract/Free Full Text] - CHARM Investigators and Committees. Yusuf S., Pfeffer M.A., Swedberg K., et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet (2003) 362:777–781.[CrossRef][Web of Science][Medline]
- The Merit-HF study group. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet (1999) 353:2001–2007.[CrossRef][Web of Science][Medline]
- Kalantar-Zadeh K., Block G., Horwich T., Fonarow G.C. Reverse epidemiology of conventional cardiovascular risk factors in patients with chronic heart failure. J Am Coll Cardiol (2004) 43:1439–1444.
[Abstract/Free Full Text] - Solomon S.D., St John Sutton M., Lamas G.A., et al. Ventricular remodeling does not accompany the development of heart failure in diabetic patients after myocardial infarction. Circulation (2002) 106:1251–1255.
[Abstract/Free Full Text] - Kenchaiah S., Evans J.C., Levy D., et al. Obesity and the risk of heart failure. N Engl J Med (2002) 347:305–313.
[Abstract/Free Full Text] - Horwich T.B., Fonarow G.C., Hamilton M.A., MacLellan W.R., Woo M.A., Tillisch J.H. The relationship between obesity and mortality in patients with heart failure. J Am Coll Cardiol (2001) 38:789–795.
[Abstract/Free Full Text] - Horwich T.B., Hamilton M.A., Maclellan W.R., Fonarow G.C. Low serum total cholesterol is associated with marked increase in mortality in advanced heart failure. J Card Fail (2002) 8:216–224.[CrossRef][Web of Science][Medline]
- Weinberg E.O., Mirotsou M., Gannon J., Dzau V.J., Lee R.T., Pratt R.E. Sex dependence and temporal dependence of the left ventricular genomic response to pressure overload. Physiol Genomics (2003) 12:113–127.
[Abstract/Free Full Text] - Haghighi K., Schmidt A.G., Hoit B.D., et al. Superinhibition of sarcoplasmic reticulum function by phospholamban induces cardiac contractile failure. J Biol Chem (2001) 276:24145–24152.
[Abstract/Free Full Text] - Dash R., Schmidt A.G., Pathak A., et al. Differential regulation of p38 mitogen-activated protein kinase mediates gender-dependent catecholamine-induced hypertrophy. Cardiovasc Res (2003) 57:704–714.
[Abstract/Free Full Text] - Leinwand L.A. Sex is a potent modifier of the cardiovascular system. J Clin Invest (2003) 112:302–307.[CrossRef][Web of Science][Medline]
- Kass D.A., Bronzwaer J.G., Paulus W.J. What mechanisms underlie diastolic dysfunction in heart failure? Circ Res (2004) 94:1533–1542.
[Abstract/Free Full Text] - Hay I., Rich J., Ferber P., Burkhoff D., Maurer M.S. The role of impaired myocardial relaxation in the production of elevated left ventricular filling pressure. Am J Physiol Heart Circ Physiol (2005) 288:H1203–H1208.
[Abstract/Free Full Text] - Skaluba S.J., Litwin S.E. Mechanisms of exercise intolerance: insights from tissue Doppler imaging. Circulation (2004) 109:972–977.
[Abstract/Free Full Text] - Fischer M., Baessler A., Hense H.W., et al. Prevalence of left ventricular diastolic dysfunction in the community. Results from a Doppler echocardiographic-based survey of a population sample. Eur Heart J (2003) 24:320–328.
[Abstract/Free Full Text] - Alpert M.A., Terry B.E., Mulekar M., et al. Cardiac morphology and left ventricular function in normotensive morbidly obese patients with and without congestive heart failure, and effect of weight loss. Am J Cardiol (1997) 80:736–740.[CrossRef][Web of Science][Medline]
- Perhonen M.A., Zuckerman J.H., Levine B.D. Deterioration of left ventricular chamber performance after bed rest: "cardiovascular deconditioning" or hypovolemia? Circulation (2001) 103:1851–1857.
[Abstract/Free Full Text] - Arbab-Zadeh A., Dijk E., Prasad A., et al. Effect of aging and physical activity on left ventricular compliance. Circulation (2004) 110:1799–1805.
[Abstract/Free Full Text] - Lakatta E.G., Yin F.C. Myocardial aging: functional alterations and related cellular mechanisms. Am J Physiol (1982) 242:H927–H941.[Web of Science][Medline]
- Yelamarty R.V., Moore R.L., Yu F.T., Elensky M., Semanchick A.M., Cheung J.Y. Relaxation abnormalities in single cardiac myocytes from renovascular hypertensive rats. Am J Physiol (1992) 262:C980–C990.[Web of Science][Medline]
- Nishikawa N., Yamamoto K., Sakata Y., et al. Differential activation of matrix metalloproteinases in heart failure with and without ventricular dilatation. Cardiovasc Res (2003) 57:766–774.
[Abstract/Free Full Text] - Diamant M., Lamb H.J., Groeneveld Y., et al. Diastolic dysfunction is associated with altered myocardial metabolism in asymptomatic normotensive patients with well-controlled type 2 diabetes mellitus. J Am Coll Cardiol (2003) 42:328–335.
[Abstract/Free Full Text]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  R. Wachter, S. Schmidt-Schweda, D. Westermann, H. Post, F. Edelmann, M. Kasner, C. Luers, P. Steendijk, G. Hasenfuss, C. Tschope, et al. Blunted frequency-dependent upregulation of cardiac output is related to impaired relaxation in diastolic heart failure Eur. Heart J., August 30, 2009; (2009) ehp341v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. W. De Keulenaer and D. L. Brutsaert The Heart Failure Spectrum: Time for a Phenotype-Oriented Approach Circulation, June 23, 2009; 119(24): 3044 - 3046. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kamalesh Diabetes and prognosis: are systolic and diastolic heart failure different? Heart, February 1, 2009; 95(3): 178 - 179. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Tretjak and M. Kozelj Tissue Doppler annular velocities, NT-proBNP and exercise capacity in healthy elderly Age Ageing, May 1, 2008; 37(3): 336 - 339. [Full Text] [PDF]
|
|
|
|
 |
|
 R. W. Schrier Decreased Effective Blood Volume in Edematous Disorders: What Does This Mean? J. Am. Soc. Nephrol., July 1, 2007; 18(7): 2028 - 2031. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||