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European Journal of Heart Failure 2002 4(4):419-430; doi:10.1016/S1388-9842(02)00020-X
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© 2002 European Society of Cardiology

Diagnosing diastolic heart failure

D.J.W. van Kraaija,*, P.E.J. van Pola, A.W. Ruitersa, J.B.R.M. de Swarta, D.J. Lipsa, N. Lencera and P.A.F.M. Doevendansb

a Department of Cardiology Academic Medical Hospital Maastricht, P.O. Box 5800, 6262 AZ Maastricht, The Netherlands
b Interuniversitary Cardiology Institute of the Netherlands Utrecht, The Netherlands

* Corresponding author. Tel.: +31-43-3875-106; fax: +31-43-3875-104 E-mail address: dvankraaij{at}hotmail.com


   Abstract
Top
 Abstract
1. Introduction
 2. Pathophysiology of diastolic...
 3. Methods of diagnosing...
 4. Diagnostic criteria for...
 5. Discussion
 References
 
Background: increasing evidence supports the existence of left ventricular diastolic dysfunction as an important cause of congestive heart failure, present in up to 40% of heart failure patients.

Aim: to review the pathophysiology of LV diastolic dysfunction and diastolic heart failure and the currently available methods to diagnose these disorders.

Results: for diagnosing LV diastolic dysfunction, invasive hemodynamic measurements are the gold standard. Additional exercise testing with assessment of LV volumes and pressures may be of help in detecting exercise-induced elevation of filling pressures because of diastolic dysfunction. However, echocardiography is obtained more easily, and will remain the most often used method for diagnosing diastolic heart failure in the coming years. MRI may provide noninvasive determination of LV three-dimensional motion during diastole, but data on correlation of MRI data with clinical findings are scant, and possibilities for widespread application are limited at this moment.

Conclusions: in the forthcoming years, optimal diagnostic and therapeutic strategies for patients with primary diastolic heart failure have to be developed. Therefore, future heart failure trials should incorporate patients with diastolic heart failure, describing precise details of LV systolic and diastolic function in their study populations.

Key Words: Diastolic heart failure • Echocardiography • Heart failure pathophysiology • Left ventricular diastolic dysfunction • Review

Received July 19, 2001; Revised October 22, 2001; Accepted December 20, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Pathophysiology of diastolic...
 3. Methods of diagnosing...
 4. Diagnostic criteria for...
 5. Discussion
 References
 
Congestive heart failure is a major public health problem in developed countries. This disorder is a significant burden to healthcare providers and society, and has an enormous impact on quality of life for patients. It is now well recognized that the syndrome of congestive heart failure may arise in the absence of significant abnormality of left ventricular (LV) systolic function. Several epidemiological investigations have confirmed that up to half of subjects with congestive heart failure in the community may have a normal LV ejection fraction [1–4]. Many of these patients have heart failure due to LV diastolic dysfunction. Particular changes in the LV pressure volume relation cause limiting symptoms, which may only occur during exercise (LV diastolic dysfunction), but also in rest (LV diastolic heart failure). There is little information on the epidemiology of diastolic heart failure, it appears to be more prevalent in women and blacks [5,6], and there is also uncertainty about the mortality related to this disorder. However, hospitalization rates and costs for diastolic heart failure are certainly comparable to those for systolic heart failure [7].

Numerous clinical trials have documented the benefits of treatment for systolic heart failure; however, since most large trials in heart failure have excluded patients with well-preserved LV systolic function, the optimal treatment strategies for patients with primary diastolic dysfunction have not yet been defined; Research is complicated by the pathophysiologic heterogeneity of diastolic dysfunction and by the limitations of various invasive and noninvasive diagnostic modalities. Investigations have been further hampered by the lack of uniform criteria for the final diagnoses of diastolic dysfunction and diastolic heart failure. Some have argued that many patients with diastolic heart failure are mislabeled [8], others have classified diastolic heart failure as a manifestation of transient systolic LV dysfunction [9]. However, a growing body of evidence supports the existence of LV diastolic dysfunction, independent of systolic dysfunction, valvular disease or ischemia, as an important cause of congestive heart failure [10,11]. At this moment, paucity of solid data concerning diastolic heart failure precludes definitive diagnostic or therapeutic recommendations. The present paper aims at reviewing the pathophysiology of LV diastolic dysfunction and diastolic heart failure, as well as the currently available methods to diagnose these disorders. We will also summarize the diagnostic criteria for diastolic heart failure as applied in previous studies as well as those proposed for future investigations in consensus articles.


   2. Pathophysiology of diastolic heart failure
Top
 Abstract
 1. Introduction
 2. Pathophysiology of diastolic...
3. Methods of diagnosing...
 4. Diagnostic criteria for...
 5. Discussion
 References
 
In the clinical definition most often used, diastole is delineated by the onset of isovolumic relaxation and closure of the mitral valve. Applying this definition, ventricular relaxation is included in diastole, which is understandable since active myocardial relaxation influences ventricular pressures during early and mid-diastole. Diastole is traditionally divided into four phases, i.e. isovolumic relaxation, early diastolic filling, diastasis and atrial contraction. In all phases, a multitude of factors determines LV filling with a varying relative importance (Table 1). These factors overlap in time [12], and are influenced by each other, by LV systolic function, heart rate, and by the cardiac conduction system. Their final combined effect is on the transmitral pressure gradient, which actually determines LV filling.


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  		Table 1 Factors affecting LV diastolic properties by influencing transmitral pressure gradient

 
2.1. Isovolumic relaxation
Myocardial relaxation requires dissolution of the force-generating crossbridges between myosin and actin. Myocardial sarcomeres generate force under the direct control of calcium [13], and prompt relaxation demands the reduction of myocyte cytosolic calcium to its physiologically low concentrations. This is achieved by a sarcoplasmic reticulum calcium transporting ATPase that pumps calcium ions against a concentration gradient back into storage sites within the sarcoplasmic reticulum. In addition, sodium–calcium exchangers and sarcolemmal calcium pump transport calcium outward across the sarcolemma. Since myofilaments may sustain active crossbridge connections beyond the time that cytosolic free calcium has been reduced to its diastolic concentration in the normal myocardium, mechanical relaxation will be limited by the myofilaments per se, not the calcium exchange rate. In failing human heart, both myofilaments and calcium exchange pumps act more slowly, i.e. an attenuation of calcium sensitivity develops. The relative timing of crossbridge dissociation and calcium uptake may alter and the removal of calcium may become rate limiting, causing LV relaxation to decelerate [14]. Since calcium reuptake is an energy dependent process, relaxation may thus become abnormal early in several cardiac disease states; ischemia, hypertrophy and heart failure will all lead to slowing of LV relaxation [15–17].

2.2. Early diastolic filling
Early rapid filling of the LV starts with the first reversal of the atrioventricular pressure gradient opening the mitral valve and accelerating the blood into the ventricle. An explosive period of filling ensues during which the largest proportion (80–85%) of total LV filling occurs under physiological conditions. Filling velocity reaches its maximum when the atrioventricular pressure gradient reverses again, although fluid inertia will cause LV filling to continue. Finally, LV filling decelerates to a minimum until a third pressure gradient reversal occurs at the beginning of diastasis [18]. Thus, the instantaneous atrioventricular pressure gradient determines flow during the rapid filling phase. The acceleration of early flow will be determined by the rate of ventricular relaxation and left atrial pressures resulting from loading conditions and atrial and pulmonary vein compliance [19]. The interaction of active relaxation with passive ventricular compliance will mainly determine the characteristics of the deceleration of early flow and mid-diastolic flow patterns. The compliance of the LV is defined by its material properties, and can be described by several mathematical formulations fitting the passive LV pressure volume relation. The ventricular chamber probably also possesses viscoelastic properties, rendering the pressure required to fill the LV proportional to the rate at which it is filled. However, there is some evidence, that viscoelasticity is insignificant at small volumes and its effects on pressure volume relations are minimal [20]. Finally, although incompletely understood, LV diastolic suction may contribute to the process of early diastolic filling [21–23].

2.3. Diastasis and atrial contraction
Diastole further encompasses diastasis and the atrial contraction phase. On a time scale, their duration mainly depends on heart rate and on the duration of systole, and at normal heart rates, this will correspond to approximately 50% of the total duration of the cardiac cycle. On a volume scale however, only the last 5–15% of ventricular filling occurs during diastole. It has been advocated, that only diastasis and atrial contraction represent true diastole physiologically, and it is certainly true that filling of the ventricle during these two phases approximates best a reflection of LV passive filling characteristics. Once deceleration of early rapid filling flow is complete, LV filling enters a phase during which only a small additional volume is slowly added to the LV, accompanied by a very gradual rise in LV pressure [24]. In young volunteers, only 6% of total LV filling volume is added during diastasis in approximately 180 ms, and presently, mechanisms operating during diastasis are not considered important in overall diastolic function.

The left atrium acts as a reservoir during systole, storing blood at a certain pressure which is determined by left atrial compliance, blood that is subsequently supplied to the ventricle during diastole. The atrial contraction has a booster effect on LV filling, contributing approximately 15% of the total LV filling volume. The effectiveness of the atrial contraction is dependent on LV compliance (i.e. atrial afterload), but also atrial preload, heart rate, atrial contractility and atrial geometry. Particularly at increased heart rates, during exercise, or in case of impaired LV function, atrial contribution may be increased, thus augmenting LV filling and, through the Frank–Starling mechanism, increasing cardiac output [25]. Increase of atrial reservoir and pumping capacity will act as a first mechanism in response to impairment of LV filling in the failing heart. Eventually, left atrial dilatation and atrial afterload mismatch will result in ineffective atrial systolic function, rendering the atrium to a mere conduit for flow.

2.4. Diastolic heart failure
Conceptually, the causes of diastolic dysfunction may be subdivided into a decrease in passive myocardial diastolic compliance, and an impairment in active LV relaxation. A variety of myocardial and pericardial disorders may provoke an upward shift of the diastolic portion of the LV pressure–volume or pressure–dimension relation, resulting in relatively large changes in LV diastolic pressures for relatively small volume changes (Table 2). It is the shift in LV pressure volume relation that causes the symptoms of pulmonary congestion (i.e. dyspnea), first occurring during exercise, later also in rest. In addition, patients with diastolic dysfunction may be unable to normally augment stroke volume e.g. during exercise, even in the setting of increased ventricular filling pressure, providing a rationale for the symptoms of diminished exercise tolerance and chronic fatigue [26].


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  		Table 2 Causes of diastolic dysfunction

 

   3. Methods of diagnosing diastolic heart failure
Top
 Abstract
 1. Introduction
 2. Pathophysiology of diastolic...
 3. Methods of diagnosing...
4. Diagnostic criteria for...
 5. Discussion
 References
 
3.1. Clinical features
A diagnosis of congestive heart failure will typically be established on the basis of compatible signs and symptoms, such as exertional dyspnea, orthopnea, atrial gallop sounds, and pulmonary rales combined with a suggestive chest X-ray and a favorable response to diuretics. Differentiating between diastolic and systolic heart failure on clinical grounds is very difficult, although clues may be given by the patients past history, clinical presentation, physical examination, radiographic and electrocardiographic findings. Exertional dyspnea because of pulmonary congestion is frequently an early event in diastolic heart failure [27]. A past history of hypertension, or the presence of LV hypertrophy on the electrocardiogram and a small heart on chest X-rays may all suggest diastolic dysfunction in a heart failure patient. However, Vasan et al. reported considerable disagreement among studies examining clinical predictors of normal systolic function in patients with congestive heart failure, and they concluded that clinical features and physical examination fail to discriminate between heart failure patients with and without intact LV systolic function [5].

3.2. Invasive diagnostic methods
The definite diagnosis of diastolic dysfunction or failure depends on the observation of an inappropriate upward shift of the (end-)diastolic pressure–volume relation. Thus, objective evidence of ventricular diastolic dysfunction requires cardiac catheterization with volume determinations using frame-by-frame analysis of LV contrast angiograms or impedance measurements and high-fidelity measurements of ventricular pressure with a micromanometer [28–31]. Plotting pressure and volume simultaneously, a phase space diagram is created, that can be used to analyze diastolic (as well as systolic) ventricular function during the cardiac cycle (Fig. 1). At end diastole, isovolumic contraction causes an abrupt increase in ventricular pressure with little change in LV volume (point A). Systolic ejection begins after opening of the aortic valve, when LV pressure exceeds aortic pressure (point B). LV volume decreases rapidly, and at end ejection LV pressure again decreases below aortic level (point C), whereafter isovolumic relaxation begins with a rapid decrease in ventricular pressure. Reduction of LV pressure below the atrial level causes the mitral valve to open, and ventricular diastolic filling begins (point D). Finally, the pressure–volume loop is completed by a large increase in ventricular volume with a minimal increase in LV pressure during the rapid filling phase, diastasis and atrial contraction.


Figure 1
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  		Fig. 1 Schematic diagram of left ventricular (LV) pressure volume curve. Points A, B, C and D represent end diastole, beginning of systolic LV ejection, LV end ejection, and isovolumic relaxation phase, respectively (see text). ESP, end-systolic pressure; EDV, end-diastolic volume.

 
The rate of isovolumic pressure decrease is often assessed by the minimum value of the first derivative of ventricular pressure with respect to time (dP/dtmin). The rate of LV pressure decline from minimum to mitral valve opening follows a monoexponential time course and can also be assessed by computing its time constant ({tau} or tau), following the equation P=P0 · e–t/{tau}+P{infty}, in which P=ventricular pressure; P0=ventricular pressure at dP/dtmin; t=time after dP/dtmin; {tau}=relaxation time; and P{infty} is the asymptote pressure in the absence of filling [28,32]. An increase in {tau} reflects a delay in relaxation. Characterization of early diastolic filling requires continuous measurement of LV volume. Peak early filling rate, peak velocity of early diastolic filling, the velocity–time integral, percentage of total diastolic filling time occupied by rapid LV filling, and measurements of time intervals between diastolic events can all be used to assess the early phase of diastole. However, the accuracy of these variables depends on the geometric assumptions used to estimate LV volume [33].

LV chamber compliance can be defined as the ratio of change in volume unit to unit change in pressure (dV/dP), and requires an exponential curve fit to the diastolic LV pressure–volume relation. A constant of LV chamber stiffness can be derived by logarithmic transformation of the exponential equation, P=P0 · eb · V+C, in which P=ventricular pressure; P0=ventricular pressure at zero volume; b=the constant of chamber stiffness; V=ventricular volume; and C=the pressure asymptote [28]. The mean value for the chamber stiffness constant in control subjects is 0.21±0.03, with an upper range of 0.27 [34,35]. Chamber stiffness varies along the LV pressure–volume curve, and a comparison of chamber compliances requires normalization to LV filling pressure [36]. Parallel position shifts in the pressure–volume loop during diastole may not reflect in measurements of chamber stiffness. For example, an acute increase in pericardial pressure will shift the pressure volume diagram upward, although the intrinsic LV compliance, i.e. the slope of the dV/dP versus pressure relation, will not alter. Therefore, both the position of the pressure volume curve and the slope of the pressure volume relation are important in assessing LV function during diastole [37,38].

The material properties of the myocardium itself, i.e. myocardial stiffness as defined by its resistance to stretch, can be quantitated by examining the ventricular wall stress–strain relationship during diastole [33]. Again by use of an exponential equation, the stress–strain relationship can be described, deriving the constant of myocardial stiffness (b') [28], reported to equal 9.9±3.3 in a control group [39]. If comparisons are made under conditions of similar ventricular wall stress and geometry, LV chamber stiffness appears to be directly proportional to myocardial stiffness [29]. Regional inhomogeneity of ventricular stiffness should also be taken into account. Finally, myocardial viscoelasticity may alter ventricular filling to some degree, although this alteration is small in the normal functioning heart [20].

Given the myriad of interacting factors controlling diastole, it appears unlikely that any single index describing LV diastolic function adequately will ever be derived. Although cardiac catheterization probably provides our best approximation of a definite diagnosis of diastolic heart failure, it is not feasible to perform this procedure in all patients with (suspected) diastolic dysfunction, or to repeat invasive investigations to evaluate various interventions. Typically, patients will not be congested and clinically stable before an invasive procedure, limiting its sensitivity [31]. In addition, even with precise measurements of ventricular chamber pressures and volumes, diastolic abnormalities may be functional or transient, making the timing of clinical or investigative studies of critical importance [9].

3.3. Non-invasive diagnostic methods
3.3.1. Echocardiography
Since the 1980s, Doppler echocardiography has enabled measurement of LV filling patterns by analyzing and quantifying the velocity profile of the blood flowing from left atrium to left ventricle through the mitral valve. Doppler-derived assessment of LV filling correlates well with invasive and radionuclide measurements of LV volume change during diastole [40–42]. Typically, blood flow velocity across the mitral valve will demonstrate a biphasic pattern, in which an early peak flow occurs during rapid early diastolic filling (peak E) and a late peak occurs during atrial systole (peak A). Many other Doppler derived indices of diastolic filling have been proposed [24,43–45], of which deceleration time (the time interval of peak E wave velocity to zero) and isovolumic relaxation time (the time from the end of systolic ventricular outflow to mitral valve opening, abbreviated as IVRT) are applied most often. Many authors have reviewed three characteristic abnormal LV diastolic filling patterns [41,46–49]. In healthy young subjects, LV relaxation is rapid, and most of ventricular filling occurs in early diastole. Mitral flow velocity recordings demonstrate a high E/A velocity ratio above 1, short isovolumetric relaxation time and short deceleration time. With advancing age, but also because of ventricular ischemia or hypertrophy, LV relaxation will progressively slow, and early diastolic pressure gradient will decrease. This leads to a compensatory increase in atrial contribution to LV filling, reversing the E/A ratio below 1, increasing deceleration time and IVRT. This first abnormal filling LV filling pattern has also been called ‘delayed relaxation’ (Fig. 2).


Figure 2
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  		Fig. 2 Schematic representation of four characteristic mitral inflow patterns. E, early peak; A, atrial peak; DT, deceleration time (ms).

 
A second pattern of abnormal LV filling has been termed ‘pseudo-normalization’, because of an apparently normal E/A ratio greater than 1. This pattern results from an increase in left atrial pressure compensating for slow relaxation. Early deceleration time and IVRT may be normal or shortened, and this pattern may be difficult to distinguish from normal LV filling. The presence of enhanced flow reversal in the pulmonary veins after atrial contraction or inversion of the E/A ratio during a Valsalva's maneuver may aid in detecting this filling pattern, which could be considered as an intermediate stage between impaired relaxation and restrictive LV filling.

In the third abnormal ventricular filling pattern, also termed ‘restrictive filling’, ventricular pressures will rapidly increase during early diastole, and subsequent filling will be minimal, causing an increased E/A ratio, often above 2, with a short deceleration time and IVRT. Ventricular pressures may exceed atrial pressures during diastole resulting in mitral and tricuspid regurgitation. Isovolumic relaxation time (normal range 60–90 ms) reflects myocardial relaxation, and is the first to become abnormal in case of impaired ventricular relaxation [50]. However, it is dependent on afterload and heart rate [51]. The deceleration time (normal range 193±23 ms), affected by ventricular stiffness and atrial and ventricular pressures, may be of use in assessing rapid filling rate.

Further echocardiographic examinations may aid in the analysis of diastolic filling patterns. Transesophageal echocardiography can be applied to assess pulmonary venous flow velocity patterns in detail, and color kinesis and Doppler tissue imaging may be used to obtain quantitative data on both regional and global LV wall motion [52]. Color Doppler M-mode assessment of flow propagation velocity and early diastolic annular velocity can be used to estimate LV filling pressures [53]. The mitral annular motion as depicted with Doppler tissue imaging has been demonstrated to be abnormally low and relatively independent of preload in patients with pseudonormal and restricted filling patterns [54,55]. The time constant of relaxation ({tau}) may be non-invasively calculated by determining relaxation velocities in the myocardium [56,57].

Aging, disease progression, and changes in loading conditions may lead to variable combinations of LV relaxation, chamber stiffness, and atrial to ventricular pressure gradients causing transition from one filling pattern into another. Progressive hemodynamic deterioration may cause an evolution of transmitral flow patterns as described above, but specific clinical situations may alter this sequence. A certain pattern of LV diastolic filling will always result from a complex interaction of various factors such as heart rate and rhythm, preload, aortic or mitral valve disease, right ventricular competence, ventricular septal interaction, active LV relaxation, LV elasticity properties, and left atrial contraction. Rapid volume loading in a healthy volunteer will increase left atrial pressures, lower the atrial to ventricular pressure gradient and may cause a restrictive appearing LV diastolic filling pattern [58], whereas diuretic therapy decreasing left atrial pressure may result in a shift from a pseudonormalized filling pattern to a pattern of slow relaxation and delayed filling. Thus, non-invasive Doppler measurements of ventricular inflow will never provide direct assessment of systolic relaxation or diastolic compliance and should always be interpreted with caution. A further problem is the occurrence of atrial fibrillation or frequent ectopic beats, necessitating averaging of several heart cycles with equal RR intervals.

3.3.2. Exercise testing
Normal hemodynamic response to bicycle exercise in healthy volunteers is accompanied by a more than sevenfold increase in oxygen consumption, which is achieved by increases in cardiac index and arteriovenous oxygen difference. Both increased heart rate and enlarged stroke volume contribute to the augmentation of cardiac output. During low levels of exercise, stroke volume is increased by the Frank–Starling mechanism, with small increases in pulmonary wedge pressure leading to augmentation of enddiastolic volume. During high levels of exercise, stroke volume is mainly increased by enhanced contractility with decreases in endsystolic volumes [59,60]. In patients with systolic heart failure, increases in LV enddiastolic volumes are more pronounced, enabling the Frank–Starling mechanism to compensate for reduced inotropic reserves [61,62].

Kitzman et al. studied seven heart failure patients with a preserved LV systolic function [26], exhibiting marked exercise intolerance with a 48% reduction in peak oxygen consumption. At rest, the patients did not differ from healthy volunteers with regard to cardiac index, central arteriovenous oxygen saturation difference, stroke volume index or heart rate. During exercise however, stroke volume did not increase, resulting in a reduced cardiac index, proportionate to the reduction in peak oxygen consumption. Left ventricular ejection fraction and LV endsystolic volumes and their changes from rest to peak exercise were not different in patients compared to healthy controls. However, LV end-diastolic volumes were markedly reduced during submaximal and peak exercise, and this correlated strongly with the changes in stroke volume and cardiac index during exercise. Pulmonary wedge pressures were mildly increased in the patients at rest, but became markedly elevated during exercise. The exaggerated increases in pulmonary wedge pressure were not accompanied by an increase in LV end-diastolic volumes, meaning that these patients were unable to augment stroke volume by the Frank–Starling mechanism.

Although these studies emphasize the importance of the diastolic pressure–volume relationship in determining exercise performance, elevated wedge pressures may not be the primary cause of exercise intolerance; resting wedge pressures have been correlated with exercise intolerance, but exercise wedge pressures have not [63–65]. Others have demonstrated that excess ventilation is related to pulmonary hypoperfusion and reduced cardiac output rather than elevated LV filling pressures [64,66]. A decrease in cardiac output might thus cause skeletal muscle hypoperfusion, stimulating anaerobic metabolism and generation of lactate thus producing a sensation of fatigue [67]. Nevertheless, abnormalities of diastolic function are an important determinant of exercise intolerance in patients with heart failure [27,68–70]. In the presence of a normal LV systolic function, exercise testing may become an important aid in the diagnosis of diastolic heart failure, differentiating it from other causes of exertional dyspnea.

3.3.3. Magnetic resonance imaging
Magnetic resonance imaging (MRI) offers promising opportunities for cardiac imaging because of the intrinsic contrast that exists between soft tissue and flowing blood, although its clinical relevance needs further elucidation [71]. Currently, MRI is an established and accurate method for measuring left and right ventricular volumes and mass, as well as for determining LV ejection fraction by applying Simpson's rule to multiple tomographic planes [72,73]. MRI may have advantages over other noninvasive methods for determining LV volumes, ejection fraction, and cardiac output in patients with atrial fibrillation [74]. Left ventricular wall thickness and mass may be assessed by MRI with greater accuracy compared to echocardiographic results. A comparison of both methods in determining wall thickness in patients with hypertrophic cardiomyopathy demonstrated greater discrepancy with increasing distance from the echocardiographic transducer [75]. In the abnormal ventricle, MRI appears superior in the quantification of LV mass, because no invalid geometric assumptions are made [75].

MRI also allows for noninvasive determination of LV three-dimensional motion by labeling specific myocardial regions with a rectangular or radial grid (‘tagging’). A magnetic tag is a spatially encoded magnetic saturation plane created within tissues acting as a temporary marker [76]. The motions of any tagged structure can be tracked independently of LV chamber geometry, and myocardial tagging is now an established method for evaluation of regional myocardial contraction [77]. By tagging, a systolic wringing and diastolic untwisting motion of the LV have been demonstrated, and these motions may be profoundly altered in hearts with diastolic dysfunction [78–80]. Phase contrast MRI can also be applied to measure early and late diastolic ventricular inflow. Doppler assessments of these flow velocities are influenced by the angle between the blood flow jet and the ultrasonic beam. By measuring inflow along three-dimensional particle traces generated from MRI-data without constraint to a single line, errors may be avoided, since maximal early and late velocities are measured wherever they occur in the ventricle [81].


   4. Diagnostic criteria for diastolic heart failure
Top
 Abstract
 1. Introduction
 2. Pathophysiology of diastolic...
 3. Methods of diagnosing...
 4. Diagnostic criteria for...
5. Discussion
 References
 
4.1. Previous and ongoing studies
Vasan et al. reviewed 31 studies of CHF with normal LV systolic function published between 1970 and 1995, mostly clinical comparative studies, mostly hospital-based [5]. Apart from a striking lack of uniformity in the criteria for congestive heart failure that were applied in these studies, they found that only three of 31 studies provided details regarding the exclusion of alternative explanations for dyspnea, which is essential, since the signs and symptoms of congestive heart failure are nonspecific. In addition, only six of 31 studies assessed ventricular diastolic function in a satisfactory manner, whereas in most studies the mere presence of a normal LV systolic function was considered synonymous with diastolic heart failure. In these studies, a LV ejection fraction above a certain cut-off point (e.g. 45%) was used as inclusion criterion. Vasan et al. concluded, that the lack of consensus and subsequent heterogeneity in previous studies emphasize the need for prospective and uniform evaluation of patients with diastolic heart failure to better characterize epidemiology and natural history, as well as optimal treatment [5].

In two ongoing studies of ACE inhibitors in diastolic heart failure, the investigators have already provided specified reports of the in- and exclusion criteria, which will be applied to patients to allow for participation. In the PEP-CHF study, perindopril will be compared to placebo in elderly patients with chronic heart failure in the absence of any major LV systolic dysfunction [82]. The investigators aim to recruit one thousand patients over the age of 70 years into their study, and will follow-up on these patients for at least one year. Primary end-point of the study is the time to first occurrence of a combined end-point of total mortality and unplanned heart failure related hospital admission. The latter includes hospitalization due to an increase in severity of the heart failure signs or symptoms, hospitalization for declining renal function or acute myocardial ischemic events or arrhythmias that are associated with worsening of heart failure, as well as admissions because of other problems, such as infections, that lead to an exacerbation of congestive heart failure. Secondary outcome measures in this study include death, an increase in diuretic treatment of over 40 mg furosemide per day (or equivalent) or new initiation of combination therapy with thiazide diuretics, cardiovascular mortality, and changes in symptom score, quality of life or NYHA heart failure score.

The PEP-CHF study requires clinical and echocardiographic evidence of cardiac dysfunction rather than the mere absence of systolic dysfunction for inclusion. A first report on the ongoing screening process reports of considerable numbers of patients excluded because of comorbidity and significant systolic dysfunction. This suggests, that the use of positive echo criteria for diastolic dysfunction may lead to a lower proportion of patients with a diagnosis of diastolic heart failure than in previously reported series. However, as the research group comments, the need for studies of the elderly heart failure population with its comorbidity and functional impairments remains irrefutable [83].

The Hong Kong Diastolic Heart Failure study has already started in May 1999, and includes patients who have clinical evidence of heart failure documented by typical symptoms and signs, and radiological evidence of pulmonary venous congestion, combined with a LV ejection fraction over 45% as measured by echocardiography [84]. Patients are randomized to diuretics alone, diuretics plus ramipril, or diuretics plus irbesartan. The investigators also plan to recruit approximately 1000 patients, 300 in each group. The primary end-point is again a combination of mortality and episodes of hospitalization, with secondary end-points being quality of life and exercise capacity as measured by a validated questionnaire and 6-min walking tests, respectively.

4.2. Consensus proposals
The European Study Group on Diastolic Heart Failure states that diagnostic criteria for diastolic heart failure should reflect underlying pathophysiologic mechanisms, be readily obtainable with modern diagnostic tools, and be applicable to different cardiac diseases featuring diastolic heart failure [28]. The diagnostic criteria proposed by the Study Group (Table 3) do not include diastolic LV dysfunction in the presence of systolic cardiac failure. The criteria are largely dependent on echocardiographic cut-off values of several indices, which are set at the 95% confidence interval of the mean value of the index observed in a normal population. Wherever possible, age-related cut-off values are reported. Several indices, particularly those for abnormal LV relaxation, filling, diastolic distensibility and diastolic stiffness, are influenced by the simultaneous presence of several cardiac diseases, and the Study Group proposes adjusted criteria for diastolic heart failure in CAD (with and without previous myocardial infarction, and in acute ischemia), hypertrophic obstructive cardiomyopathy, cardiac amyloidosis, hypertensive heart disease, valvular heart disease, diabetes and cardiac transplantation.


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  		Table 3 Primary diastolic heart failure criteria proposed by European Study Group on Diastolic Heart Failure [28]

 
In a recent proposal for uniform diagnostic criteria for diastolic heart failure, it is stated that the diagnosis of congestive heart failure is primarily clinical [31]. Although assessment of LV systolic function is critical in determining optimal treatment, the diagnosis of heart failure should not be made purely on the basis of LV ejection fraction: a normal LV ejection fraction should not be used to reject a diagnosis of congestive heart failure if the clinical presentation is convincing. Concerns about false-positive diagnoses should be addressed by careful consideration and ruling out alternative diagnoses. Subsequently a classification schema for the diagnosis of diastolic heart failure is proposed (Table 4), categorizing patients according to the degree of diagnostic certainty from ‘definite’ via ‘probable’ to ‘possible’. Again, alternative causes of heart failure need to be considered, because these could exclude patients from this scheme. The diagnostic probability for diastolic heart failure may increase if the clinical setting is typical for the presence of LV diastolic dysfunction. According to the authors, this would for instance apply to a patient with a markedly elevated blood pressure during congestion, or a patient with moderate concentric hypertrophy without concomitant wall motion abnormalities on echocardiography, or if tachy-arrhythmia such as atrial fibrillation accompany congestive heart failure, or if congestive heart failure occurs after the administration of small amounts of intravenous fluid in a patient with normal LV ejection fraction. Diastolic heart failure may also become more likely if the heart failure improves with treatment directed at the underlying cause of diastolic dysfunction, such as lowering blood pressure, controlling a rapid heart rate, or restoration of atrioventricular synchrony. As the authors correctly point out, the validity of the proposed categorization scheme has yet to be determined in prospective studies.


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  		Table 4 Diastolic heart failure criteria proposal [31]

 

   5. Discussion
Top
 Abstract
 1. Introduction
 2. Pathophysiology of diastolic...
 3. Methods of diagnosing...
 4. Diagnostic criteria for...
 5. Discussion
References
 
The present paper reviews the pathophysiology of diastolic heart failure and the currently available diagnostic methods for this disorder. It also summarizes previously applied criteria as well as recent proposals for uniform diagnostic criteria. Indeed, a uniform approach to the diagnosis of diastolic heart failure in future studies appears essential. Given the prognostic consequences and emerging therapeutic implications, stratification of heart failure patients into groups with predominantly systolic dysfunction and those with primarily diastolic dysfunction will become increasingly important in the forthcoming years. However, development of truly uniform and universally accepted criteria for the diagnosis of diastolic heart failure will require extended investigations of the heterogeneous population of patients with heart failure and intact systolic function.

Retrospective and prospective population based studies are needed to provide more details both on the prevalence of alternative causes of dyspnea, as well as on the prevalence of the various etiologies leading to diastolic dysfunction and diastolic heart failure. To assess the complex pathophysiological determinants of diastolic heart failure, animal models may be an important tool, and transgenic and knockout models of cardiac hypertrophy and failure may provide important new clues on heart failure pathophysiology. Therefore, investigational models should be developed of animals with failing hearts with predominantly diastolic abnormalities in relaxation and compliance. Eventually, such investigations may also provide new biological targets for future human heart failure treatment.

In the mean time, diagnostic approaches to heart failure and diastolic heart failure in humans must be further validated. Evaluation of currently available therapeutic strategies such as ACE inhibitors and beta-blockers must be performed in well-delineated heart failure populations including patients with isolated or predominant diastolic heart failure. For diagnosing LV diastolic dysfunction, invasive hemodynamic measurements may still be considered the gold standard. However, echocardiography is a more easily obtainable diagnostic method, and will remain the most often used method for diagnosing diastolic dysfunction of the left ventricle. We do need more data on the correlation of echocardiographic findings regarding diastolic dysfunction with clinical findings and therapy response. Future studies are also needed on newer non-invasive ways of diagnosing and monitoring LV diastolic dysfunction and diastolic heart failure. For this purpose, non-invasive assessment of intracardiac pressures and volumes is essential. Exercise testing with assessment of LV volumes and pressures may be of help in detecting exercise-induced elevation of LV filling pressures because of diastolic dysfunction. MRI may provide noninvasive determination of LV three-dimensional motion during diastole, but data on correlation of MRI data with clinical findings are scant, and possibilities for widespread application are limited until now. Newer ideas on non-invasive diagnosis of diastolic dysfunction should be explored [85].

Finally, regardless of the true prevalence and importance of diastolic heart failure, awareness has increased in the past decade, that heart failure is always a result of both systolic and diastolic characteristics of the heart. Therefore, future large-scale heart failure trials will have to address this by describing precise details of ventricular systolic and diastolic function in their patient populations in stead of merely stating a low ejection fraction as a self-explanatory reason for the presence of congestive heart failure. Only this will allow clinicians to fully interpret the trial results, and to decide which medications should be prescribed to which patients, and what benefit to expect from various interventions.


   References
Top
 Abstract
 1. Introduction
 2. Pathophysiology of diastolic...
 3. Methods of diagnosing...
 4. Diagnostic criteria for...
 5. Discussion
 References
 

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