STATE-OF-THE-ART PAPER
Unlocking the Mysteries of Diastolic FunctionDeciphering the Rosetta Stone 10 Years Later
Steven J. Lester, MD, FACC, FRCPC, FASE*,*,
A. Jamil Tajik, MD, FACC*,
Rick A. Nishimura, MD, FACC ,
Jae K. Oh, MD,
Bijoy K. Khandheria, MBBS, FACC, FASE, FESC* and
James B. Seward, MD, FACC
* Division of Cardiovascular Disease, Mayo Clinic, Scottsdale, Arizona
Mayo Clinic, Rochester, Minnesota.
Manuscript received August 9, 2007;
revised manuscript received September 20, 2007,
accepted September 24, 2007.
* Reprint requests and correspondence: Dr. Steven J. Lester, Cardiovascular Diseases, Mayo Clinic Arizona, 13400 East Shea Boulevard, Scottsdale, Arizona 85259. (Email: lester.steven{at}mayo.edu).
 |
Abstract
|
|---|
It has now been a quarter of a century since the first description by Kitabatake and his associates of the use of echo-Doppler to characterize the transmitral flow velocity curves in various disease states. A decade ago we described the role of echocardiography in the "Evaluation of Diastolic Filling of Left Ventricle in Health and Disease: Doppler Echocardiography Is the Clinician’s Rosetta Stone." Over the ensuing decade, advances in echo-Doppler have helped to further decipher the morphologic and physiological expression of cardiovascular disease and unlock additional mysteries of diastology. The purpose of this review is to highlight the developments in echo-Doppler and refinements in our knowledge that have occurred over the past decade that enhance our understanding of diastology.
|
Abbreviations and Acronyms
| | A = A velocity | | ACEI = angiotensin-converting enzyme inhibitor | | ARA = aldosterone receptor antagonist | | ARB = angiotensin I receptor antagonist | | DT = deceleration time | | DTI = Doppler tissue imaging | | E = E velocity | | Ea = arterial elastance | | IVRT = isovolumic relaxation time | | LA = left atrium | | LV = left ventricle/ventricular | | LVOT = left ventricular outflow tract | | SRivr = strain rate during the isovolumic relaxation phase of the cardiac cycle | | Vp = mitral inflow propagation velocity |
|
Echo-Doppler with its high spatial and unequaled temporal resolution has revolutionized our clinical access to cardiac physiology and pathophysiology. It has now been a quarter of a century since the first description by Kitabatake et al. (1) of the use of echo-Doppler to characterize the transmitral flow velocity curves in various disease states. A decade ago we described the role of echocardiography in the "Evaluation of Diastolic Filling of Left Ventricle in Health and Disease: Doppler Echocardiography Is the Clinician’s Rosetta Stone" (2), the Rosetta Stone here being used as a metaphor to refer to anything that is a critical key to a process of decryption or translation of a difficult problem. The term "diastology" continues to refer to the science and art of characterizing left ventricular (LV) relaxation, filling dynamics, and their integration into clinical practice. The physiology of diastole remains valid as discussed a decade ago (2). However, over the ensuing decade, advances in echo-Doppler have helped to further decipher the morphologic and physiological expression of cardiovascular disease and unlock additional mysteries of diastology. The purpose of this review is to highlight the developments in echo-Doppler and refinements in our knowledge that have occurred over the past decade that enhance our understanding of diastology. Developments include:- 1 Epidemiologic studies highlighting the prevalence and prognosis of those with diastolic dysfunction with and without clinical symptoms
- 2 The concept of "continuity disease" and "clustering"
- 3 Noninvasive measures of the acuity and chronicity of LV filling pressure elevation
- 4 Concepts of blood flow propagation within the LV
- 5 Stress testing, diastolic function response
- 6 The integration of echo-Doppler measures of diastolic function into a therapeutic treatment paradigm
- 7 Better understanding of the relationship of myocardial form with function and the ability to characterize measures of myocardial mechanics
|
Epidemiology
|
|---|
Over the past decade, there has been a steady rise in the prevalence of heart failure in those with a preserved LV ejection fraction (diastolic heart failure) (3). By the seventh decade of life, the incident cases of heart failure with a preserved LV ejection fraction approach, and by the eighth decade of life exceed, those of heart failure with reduced LV ejection fraction (4). The survival of patients with the clinical syndrome of heart failure is similar in those with persevered versus those with a reduced LV ejection fraction (5). The understanding of diastology has become even more germane to the practice of medicine as our understanding evolves of the profound adverse clinical consequences of clinically overt diastolic dysfunction and that the prevalence of asymptomatic diastolic dysfunction in the general community is not insignificant, a finding being noted in approximately 25% to 30% of individuals  45 years of age (6,7). Note, diastolic dysfunction and diastolic heart failure are not interchangeable terms. Diastolic heart failure is used to describe clinically symptomatic individuals with the characteristic syndrome of heart failure in the setting of a normal ejection fraction, whereas diastolic dysfunction simply denotes an abnormality of diastolic function and does not characterize the clinical status of an individual.
|
"Continuity Disease"
|
|---|
The cardiovascular system is a continuous system of reservoir, pump, and vessels. An ailment in one part of the system will influence all contiguous components. An increase in vascular and ventricular stiffness is an integral component of aging (8–12). Vascular and ventricular stiffness appear to be a precipitant to impaired cardiac performance and clinical prognosis. Vascular stiffness histologically is associated with changes in vessel wall architecture and perivascular fibrosis (13). A change in the extracellular matrix of the myocardium, with the formation of excess collagen tissue and serologic evidence of an active fibrotic process, is a characteristic finding in those with diastolic dysfunction (14,15). At the cellular level, there is reduced phosphorylation of sarcomeric proteins (16) and at the proteomic level, an isoform change in important structural proteins such as titin, which functions to connect sarcomeres at their ends (Z-discs) and participates in cell signaling (15,17,18). The change in cardiovascular elastance is a marker for increased cardiac morbidity, and not surprisingly, it appears to be most prevalent in that segment of the community most likely to develop the clinical syndrome of heart failure independent of the underlying LV ejection fraction (11).
Effective arterial elastance (Ea) can be estimated as the ratio of end-systolic pressure/stroke volume (19). End-systolic pressure is estimated as (0.9 x systolic blood pressure) and stroke volume the product of the left ventricular outflow tract (LVOT) area and LVOT time velocity integral. During diastole, when the mitral valve is open, the left atrium (LA) is exposed to the loading pressure within the LV. Over time, exposure of the LA to increased filling pressure will result in its remodeling reflected in the measure of LA volume. A simple yet robust marker for the chronicity of change in Ea appears to be the LA size. In clinical practice, LA size expressed as volume indexed to body surface area is recommended (20,21). The biplane area-length or Simpson’s methods are a practical means with which to measure LA volume (Fig. 1).
View larger version (80K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1 Biplane Methods With Which to Calculate LA Volume
(A) Biplane area length, A1 = left atrial (LA) area, 4-chamber view; A2 = LA area, 2-chamber view; L1 and L2: length from midplane of mitral annulus to superior LA, L = LA length, L1 or L2 whichever is shorter; (B) Biplane Simpson’s where the volume of the LA is calculated as the sum of the volume of each individual disc.
|
|
The LA volume can be viewed as a morphologic expression of LV diastolic dysfunction. Left atrial volume is regarded as a "barometer" of the chronicity of diastolic dysfunction and to analogize, LA volume is to diastolic function and to all forms of heart disease as the HbA1c is to diabetes. This simple measure of LA volume provides significant insight into an individual’s risk for the development of adverse cardiovascular events including, myocardial infarction, stroke, atrial fibrillation, and heart failure (22–25). Left atrial volume is graded relative to risk, 28 to 33 ml/m2 = mild; 34 to 39 ml/m2 = moderate; and 40 ml/m2 = high or severe (23). For the practicing cardiologist, LA volume, therefore, may be considered an excellent biomarker of the chronicity of diastolic dysfunction and of cardiovascular disease risk (26).
|
Blood Flow and Myocardial Tissue Velocities
|
|---|
An enlarged LA reflects chronicity of LV filling pressure elevation while Doppler-derived LV filling dynamics, which reflect acuity, can vacillate moment to moment. An integrative evaluation of acuity and chronicity allows for clinical staging of diastolic dysfunction (Fig. 2). The strengths and weaknesses of various parameters used in the evaluation of LV filling pressure are outlined in Table 1
and discussed in the following text.
View larger version (62K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 2 The Natural History of Diastolic Function and LV Filling
DD = diastolic function; e' = early diastolic mitral annular velocity; LAP = left atrial pressure; LV = left ventricular.
|
|
The mitral inflow velocity profile is used to initially characterize LV filling dynamics. The E velocity (E) represents the early mitral inflow velocity and is influenced by the relative pressures between the LA and LV, which, in turn, are dependent on multiple variables including LA pressure, LV compliance, and the rate of LV relaxation. The A velocity (A) represents the atrial contractile component of mitral filling and is primarily influenced by LV compliance and LA contractility. The deceleration time (DT) of the E velocity is the interval from peak E to a point of intersection of the deceleration of flow with the baseline and it correlates with time of pressure equalization between the LA and LV (Fig. 3). As the early LA and LV filling pressures either evolve toward or away from equivalence, so will the DT either shorten or lengthen respectively.
Diastolic dysfunction is directly related to the reduction in early LV relaxation compromising the effective transfer of the blood from the atrial reservoir into the LV cavity. The reduction in LV relaxation may be characterized through the evaluation of mitral annular motion, generally with Doppler tissue imaging, which can resolve subtle changes in LV relaxation by identifying a low septal annular early diastolic mitral annular motion (e') velocity (<10 cm/s). There are 2 fundamental causes of delayed LV relaxation and elevation of early LV filling pressure:- 1 The LV chamber is distorted (e.g., infarction, hypertrophy, cardiomyopathy, and dyssynergic wall motion), impairing the effective transfer of blood from the mitral orifice to the LV apex.
- 2 The LV ejection period is prolonged due to increased ventricular-arterial afterload.
Incomplete or delayed relaxation causes a delay in the transfer of blood from atria to ventricle. The pressures impeding forward flow are reflected backward (continuity disease) into the atria and pulmonary veins. Early in the evolution of "diastolic dysfunction" the delay in emptying (DT >240 ms) is partially compensated by a more vigorous end-diastolic atria contraction, and, hence, the E/A ratio is reduced (<0.9, grade I diastolic dysfunction). With further increased impedance to atrial emptying, atrial pressure increases, and the relative difference between atria and ventricular pressure decreases (DT shortens). As a result, the E velocity and E/A ratio will now increase, and the mitral inflow velocity profile may appear normal (E/A = 0.9 to 1.5 and DT = 160 to 240, grade II diastolic dysfunction). However, the e' velocity will remain reduced, identifying the underlying LV relaxation abnormality. A reduced e' velocity, increased E/e' ratio, and associated increased LA volume (>28 ml/m2) can, therefore, be readily used to discriminate an individual with normal versus grade II (pseudonormal) diastolic dysfunction (27,28). Similarly, individuals with grade III diastolic dysfunction, E/A >2, and DT <160 ms who are able to favorably influence their mitral inflow velocity profile with hemodynamic manipulation, often the Valsalva maneuver, declare themselves of less severe diastolic dysfunction than those with grade IV diastolic dysfunction who have an irreversible restrictive pattern and a very poor prognosis.
Insights into LV diastolic function can be deciphered through the evaluation not only of the relationship of the amplitude of E to e' but also through the evaluation of the relationship of the timing of the onset of E to the onset of e'. Normally mitral inflow is initiated with rapid LV relaxation and "suction" of blood into the LV. When this occurs, the onset of e' will be slightly before or simultaneous with the onset of E. If, however, LA pressure is elevated and LV relaxation reduced, E velocity onset may precede the onset of e'. These timing relationships have been correlated with LV filling pressure (29,30) (Fig. 4).
View larger version (92K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 4 Transmitral Doppler and Tissue Doppler of the Mitral Annulus
(A) Normal left ventricular filling pressure. (Left) Mitral inflow velocity profile; (right) septal annular tissue velocity profile. (B) Elevated left ventricular filling pressure. e' = early diastolic mitral annular velocity; other abbreviations as in Figure 3.
|
|
A limitation of the use of the e' velocity is the fact that acquisition is generally from a single site, the mitral annulus, and values obtained assume that they reflect global LV relaxation. Although much less practical, the average e' velocity from multiple sites enhances the test characteristics of the E/e' ratio to predict LV filling pressures (31). The use of 2-dimensional speckle tracking technologies allows for the characterization of global parameters of myocardial motion. A measure of global diastolic strain rate during the isovolumic relaxation phase of the cardiac cycle (SRivr) directly measures a global myocardial relaxation parameter less influenced by annular and valvular pathology. The relationship of the mitral E-wave velocity to SRivr appears to provide enhanced discriminatory power with which to detect an elevation in mean pulmonary capillary wedge pressure when compared with the E/e' ratio (Fig. 5) (32).
View larger version (75K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 5 Global Strain Rate Profile
Global strain rate (SR) signal (purple, right axis), and mitral velocity (left axis) tracings by color tissue Doppler from the septal (blue) and lateral side (red) of the mitral annulus from the same cardiac cycle. Note the SR signal during the isovolumic relaxation phase of the cardiac cycle (*) and the corresponding velocity tracings from the mitral annulus recording during the same interval. Aa = late diastolic velocity; AVC = aortic valve closure; Ea = mitral annulus early diastolic velocity; GSRa = global strain rate during late left ventricular filling; GSRe = global strain rate during early left ventricular filling; GSRivr = global strain rate during the isovolumic relaxation phase of the cardiac cycle period; MVO = mitral valve opening. Reprinted, with permission, from Wang et al. (32).
|
|
Pulmonary vein flow.
The ability to evaluate myocardial motion with high temporal resolution (Doppler tissue imaging) and thus detect the underlying LV relaxation abnormality (low e') present with little exception in those with diastolic dysfunction has minimized, but not relegated obsolete, the utility of the evaluation of pulmonary vein flow in the assessment of LV filling pressure. Over the past decade, insights into the physiology of the pulmonary vein Doppler velocity profile has evolved (33). The parameters measured and insights into diastolic function gained from their interpretation, however, remain as discussed a decade ago (2). It is worthy of note that if the mitral inflow velocity profile indicates a predominant relaxation abnormality with a low E/e' ratio (normal mean LA pressure), a pulmonary vein flow duration greater than mitral inflow duration at atrial contraction may indicate an earlier stage of reduced LV compliance as well as increased LV end-diastolic pressure.
Isovolumic relaxation time (IVRT).
The IVRT is the time interval between aortic valve closure and mitral valve opening. The transducer is placed in the apical position with either a pulsed or continuous wave Doppler sample placed between the aortic and mitral valves. A normal IVRT is approximately 70 to 90 ms. The IVRT will lengthen with impaired LV relaxation and shorten when LV compliance is decreased and LV filling pressures are increased. Note the IVRT will vary with heart rate and ventricular function, and, thus, absolute values cannot always be interpreted to dichotomize normal versus abnormal LV filling pressure. Isovolumic relaxation time may be very helpful in following clinical response to various treatment strategies.
Mitral inflow propagation velocity (Vp).
Important in the mechanics of LV diastole are regional differences in myocardial relaxation. Normally there is a wave of relaxation originating at the apex and moving toward the base. This results in a base-to-apex pressure gradient allowing blood to literally be sucked into the LV. With LV diastolic dysfunction and the associated relaxation abnormality, the regional differences in relaxation are less pronounced and the intraventricular pressure gradient responsible for normal LV filling reduced or even absent.
Color M-mode of the mitral inflow obtained by placing the M-mode cursor in the direction of the mitral inflow jet seen on the color Doppler map can be used to evaluate LV relaxation (34–36). This display will provide temporal, spatial, and velocity information. There have been various methods described with which to calculate the Vp from LV base (annulus) to apex. A practical approach is to measure the slope of the line of the first aliasing velocity from the mitral valve plane to approximately 4 cm distal into the LV (normal >50 cm/s) (Fig. 6). Like e', Vp characterizes LV relaxation, and not surprising, therefore, the ratio of E/Vp can be used to estimate LV filling pressure, with an E/Vp >1.5 suggestive of a pulmonary capillary wedge pressure of >15 mm Hg (37,38). Caution in the interpretation of this ratio is recommended in the setting of LV hypertrophy and a small LV cavity size where Vp may be high and this ratio may not, therefore, accurately reflect LV filling pressure. In our clinical practice, we perform only a qualitative interpretation of the color M-mode mitral inflow velocity only providing an estimate of the velocity, temporal, and spatial distribution of LV filling.
|
Practical Approach
|
|---|
Although there are other echocardiographic parameters that may be used to characterize diastology, the parameters discussed in the preceding text represent those that are commonly used in daily practice. The measure of LA volume is the cornerstone to evaluation for its ability to provide insight into the chronicity of elevation of LV filling pressure and to characterize global cardiovascular risk.
Initial observations of 2-dimensional echocardiographic features often provide diagnostic clues as to the status of diastolic function. Patients with diastolic dysfunction qualitatively may have increased LV wall thickness, an increase in LA size, and reduced mitral annular motion. The more quantitative assessment of diastolic function and the "acuity" measure of LV filling pressure then generally begins by characterizing the mitral inflow velocity profile as either normal (E/A ratio 0.9 to 1.5, DT 160 to 240 ms), restrictive (E/A ratio typically >2, DT <160 ms), or delayed relaxation (E/A ratio <0.9, DT >240 ms). A dilemma exists when the mitral inflow velocity profile is characterized as normal and the integration of the measures of mitral inflow with measures of tissue and other blood flow velocities help to decipher normal from abnormal diastolic function (Table 2). The E/SRivr is an intellectually intriguing parameter that with further validation may become standard in the evaluation of LV filling pressures.
Although particular reference is made to the septal mitral annular e' velocity, the lateral mitral annular e' velocity may also be useful. It must be noted, however, that the lateral e' velocity generally exceeds the septal e' velocity, and, thus, in our practice a lower E/e' cutoff (12 vs. 15) is used to dichotomize normal from elevated filling pressures when the lateral e' velocity is used. The E/e' ratio derived from the septal e' is preferred (28).
When the mitral inflow velocity profile is characterized as restrictive, it too is important to integrate these findings with measures of mitral annular motion as discussed in the preceding text. With rapid relaxation (health), the LV is able to "suck" blood into itself at high velocities and the E/A ratio may exceed 2. Here, however, the rapid relaxation is clearly denoted by a robust annular e' velocity and low E/e' ratio. One important clinical caveat is constrictive pericarditis, where the e' velocity may be normal and the E/e' ratio low despite an increase in LV filling pressure ("annulus paradoxus") (39). A low e' and increase in E/e' ratio confirms a reduction in LV diastolic function and an increase in LV filling pressure.
A non–E-wave dominant mitral inflow velocity profile essentially excludes demonstrable increases in LV filling pressure. However, here too a measure of LA volume and e' is important, as there is a subset of individuals with a mitral inflow velocity profile characterizing a relaxation abnormality (grade I) diastolic dysfunction who have an increased LA volume and/or an increased septal E/e' ratio (>15, e.g., E = 80 cm/s, A = 110 cm/s, e' = 4 cm/s, E/e' = 20). We designate these individuals as having grade Ia diastolic dysfunction (mild elevation in LV filling pressure).
|
Diastolic Stress Test
|
|---|
A patient reporting symptoms of dyspnea in the setting of a normal pulmonary evaluation, a negative contemporary stress test, and normal resting diastolic function often presents a clinical enigma. Analogous to those with reactive airways disease, diastolic dysfunction my not be identified without provocation, "diastolic stress test." The mitral annular e' velocity is not significantly altered by changes in cardiac cycle length. Any change in e' velocity noted secondary to a change in cardiac cycle length is directly related to the transmitral pressure gradient as thus concordant changes in the mitral E-wave velocity are noted (40). The E/e' ratio is a representation of mean LA pressure and can be measured during an echocardiographic stress test (41,42). Mean LA pressure with exercise remains within normal limits in healthy individuals. Therefore, a measure of the E/e' ratio during aerobic stress may be useful for distinguishing patients with cardiac disease and help to solve the clinical enigma (41–44).
|
Treatment
|
|---|
In clinical medicine there are essentially only 2 therapeutic targets: to improve symptoms and, hence, quality of life, and to enhance survival, quantity of life. In those with the clinical syndrome of heart failure, it must be emphasized that heart failure is not a diagnosis but rather a constellation of signs and symptoms representing a final common pathway of a heterogeneous group of diseases (45). In those presenting with the clinical syndrome of heart failure, one must initiate a meticulous search for the underlying etiology and precipitant causes. As such, the treatment strategy must be first and foremost directed toward the identification and correction of the underlying precipitating and pathogenic mechanism(s) (Table 3). This highlights the need to individualize the therapeutic approach.
Nondisease-specific (general) therapeutic approach.
General, nondisease-specific therapies are then used to help better control symptoms. These therapies may too be tailored to an outcome of a more favorable diastolic function grade (Fig. 2). In the normal heart, as heart rate increases there is an increase in contractility and faster relaxation. In myocardial disease, there is a slower LV pressure decline and incomplete pressure restitution, and thus higher LV diastolic pressure and reduced coronary flow reserve. For individuals with grade I and II diastolic dysfunction, the duration of diastole is critical, and beta-blockers or rate-slowing calcium-channel blockers often provide a favorable symptomatic response allowing more time for ailing diastole to do its work either at rest and/or to truncate an exercise-induced increase in heart rate. In contrast, in patients with grade III or IV diastolic dysfunction, LV filling may be complete by mid-diastole. Such patients have a fixed stroke volume, and empirically slowing the heart rate into the 50s and 60s may result in a further reduction in cardiac output and a worsening of the clinical symptom complex. Therefore, in these patients, the initiation of beta-blocker therapy should be monitored closely and initiated with small doses with small increments.
Diuretics have a salutary effect on symptoms by reducing intravascular volume and steering the LV to a more favorable position on its end-diastolic pressure volume relation and reducing pericardial restraint (Fig. 7). Therapies that result simply in a change in position on the LV end-diastolic pressure volume curve without imparting a right and downward curve shift are likely analogous to treating a fever with acetaminophen; they improve the symptom but do not influence the underlying root cause and, hence, have no impact on long-term survival. Those able to respond favorably to hemodynamic manipulation do, however, appear to have a better prognosis (46–48) as they likely represent those with less severe disease. Intriguing are therapies that may favorably influence the underlying final common pathway, the increase in vascular and ventricular stiffness.
Treating the final common pathway, vascular-ventricular stiffness.
The presence of diastolic dysfunction regardless of symptom status portends significant risk for future adverse cardiovascular outcomes, and the absence of patient voiced complaints does not support the absence of therapeutic intervention. In those with clinically occult diastolic dysfunction, the initial therapeutic approach is identical to that recommended for those with symptoms: identify and treat the underlying etiology and precipitant cause(s). For example, the treatment of hypertension in those with clinically occult diastolic dysfunction results in an objective improvement in diastolic function (49). Neurohormonal modulation of the renin-angiotensin-aldosterone system is currently the only therapy with a salutary effect on some of the pathophysiological mechanisms responsible for the increase in vascular and ventricular stiffness (50,51). Angiotensin-converting enzyme inhibitors (ACEIs), angiotensin I receptor antagonists (ARBs), and aldosterone receptor antagonists (ARAs), independent of their hemodynamic effects, mediate potentially favorable effects of reduced smooth muscle cell growth, prevention of collagen deposition, reduced growth factor expression, and regression of myocardial fibrosis (52–56). The finding of an enlarged LA in the absence of a definitive underlying precipitating cause (e.g., mitral regurgitation or a high output state) is a call to arms, and our approach beyond therapeutic lifestyle intervention is to initiate ACEI or ARB therapy currently targeting a blood pressure of 110/75 mm Hg. Of interest, ACEI therapy may result in favorable remodeling of the LA independent of their influence on blood pressure (57).
In those with the clinical syndrome of heart failure and a preserved LV ejection fraction, an evidence-based approach to treatment is lacking; however, there is information supporting a clinical judgment-based approach to management. The CHARM-Preserved (Effects of Candesartan in Patients With Chronic Heart Failure and Preserved Left-Ventricular Ejection Fraction) trial, a prospective outcome trial evaluating a treatment strategy (candesartan) solely for individuals with heart failure and a normal ejection fraction, included a heterogeneous etiologic classification of heart failure (58). The findings, however, were promising, showing a significant reduction in hospitalization for heart failure and a strong trend toward significance in the primary outcome of death or hospital admission for heart failure. The PEP-CHF (Perindopril in Elderly People with Chronic Heart Failure) study evaluated individuals 70 years of age with a clinical diagnosis of heart failure and a preserved LV ejection fraction. Here too the findings were promising, showing an improvement in symptoms and exercise capacity along with fewer hospitalizations in those in the active treatment group noted in the first year of follow-up (59). We await the results of the I-PRESERVE (Irbesartan in Heart Failure with Preserved Systolic Function) trial, where inclusion defined a more discriminate patient population (60).
Statins similarly have touted favorable pleiotropic effects too on diastolic function, and the art of medicine suggests that a low threshold for the use of statins may be appropriate (61,62). Beta-blockers as discussed in the preceding text are often helpful in the symptomatic management of patients with diastolic heart failure. However, several clinical trials, again including individuals with heterogeneous pathophysiological mechanisms for heart failure, have shown that primarily those with too low an LV ejection fraction may derive a survival advantage with beta-blocker therapy (63,64). The SENIORS (Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure) trial suggests that the elderly with heart failure can tolerate beta-blocker therapy and derive a favorable clinical benefit (reduction is composite of death or cardiovascular hospitalization) particularly if target doses are achieved (65). This trial did include patients with preserved LV ejection fractions (approximately one-third), but the mean LV ejection fraction for each group was approximately 35%. Other trials have suggested that the use of beta-blockers in those with heart failure and a preserved LV ejection provides mortality benefit (66).
Endothelin influences myocardial inotropic and lusiotropic function, and intellectually intriguing is the potential role of an endothelin receptor antagonist in the management of patients with heart failure (67,68). However, when evaluated in an etiologically heterogeneous group of heart failure patients, endothelin receptor blockers when added to standard therapy did not improve outcome, currently casting doubt on the use of endothelin receptor blockers for the management of heart failure (69–71). Further pathophysiological insight into disease inception may influence novel therapeutic strategies targeting the vasculature, with end points encoded somewhere in the cardiovascular structural and functional continuum. For example, it has recently been proposed that endothelial cells may, in fact, transition into mesenchymal cells and thus contribute fibroblasts to the process of cardiac fibrosis (72). In a mouse model of pressure overload and chronic allograft rejection, recombinant human bone morphogenic protein-7 could preserve the endothelial phenotype and retard the progression of fibrosis (72). In addition, preliminary small animal studies suggest that phosphodiesterase-5A inhibition with oral sildenafil may suppress chamber and myocyte hypertrophy, remodeling, and fibrosis by deactivating various hypertrophy signaling pathways (73,74). Additional preliminary and novel strategies directed at influencing the final common pathway of disease hold promise (75). Definitive comments on the impact of beta-blockers, ACEIs, ARBs, ARAs, statins, and other pharmacologic therapies in those with heart failure and a preserved LV ejection fraction are pending prospective randomized clinical trials. Until then, such individualized treatments encompass clinical judgment-based therapeutic strategies.
|
Where Are We Going?
|
|---|
Although it is practical to classify cardiac dysfunction as either systolic or diastolic, such a classification is based on physiological principles destitute of virtue as each component of the cardiac cycle is functionally dependent on the other. Different than 2-dimensional echocardiography, where crude parameters of cardiac performance such as ejection fraction are used, Doppler echocardiography is able to detect and quantitatively display minor amplitude and temporal subtleties that may occur in ventricular mechanical function. Traditionally, parameters of diastolic function have been derived from Doppler and those of systolic function from 2-dimensional variables. This may create the illusion that individuals have "isolated diastolic dysfunction." The interrogation of cardiac function with derived parameters of deformation such as strain and strain rate confirm the illusion despite frequent pronouncement. Measures of global parameters of myocardial motion using advanced speckle tracking algorithms may allow for enhanced prediction models of LV filling pressure.
The contemporary belief is that the macro architecture of LV myofiber geometry is chiral with the subendocardial layer composed in the form of a right-handed helix gradually evolving into a left-handed helical fiber orientation in the subepicardial layer. As such, LV fiber orientation is a function of transmural location, with the fiber direction being predominantly longitudinal in the endocardial and epicardial surfaces and with the helical angle changing continuously between the endocardium and epicardium, such that the midwall fibers have a circumferential orientation forming a sort of equator of the heart (76–78). As with contraction, the endocardial and epicardial onset of relaxation is temporally discrete beginning in the apical subendocardium just before closure of the aortic valve with subepicardial relaxation beginning at the base after aortic valve closure (79). Different from contraction, however, relaxation of the helixes is in the opposite direction, apex to base for subendocardium and base to apex for subepicardium. The temporal and spatial differences in LV relaxation are critical for the creation of forces required for diastolic suction (79). Because of the intrinsic spiral geometry of the LV myofibers, shortening and lengthening of the myocardial wall results in rotary movements. The counter-directional rotation of the LV apex with respect to the base is referred to as LV twist or torsion. By convention, rotation is described from the apical end of the LV, with clockwise and counterclockwise rotations shown in negative and positive degrees, respectively (Fig. 8). Our now better understanding of myocardial form and myofiber architecture paralleled with advances in ultrasound signal processing have allowed the subtleties of myocardial motion to be characterized and quantified (80).
View larger version (68K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 8 VVI Illustrating the Rotation Motion of the LV Apex
(Left) Systole where the apical rotation is predominantly anticlockwise; (right) systole where the apical rotation (now untwisting) is predominantly in the clockwise direction. LV = left ventricular; VVI = Velocity Vector Image.
|
|
In the end, the heart is simply a pump, albeit a complex and sophisticated one that serves to deliver blood to the body. Although we can now begin to decipher the complex motion needed to complete this task, intriguing are techniques that can also decipher the complexities of the final common purpose of cardiac pump function, blood flow (81). Perhaps systolic and diastolic dysfunction will no longer be viewed clinically as dichotomous terms but rather voiced as just "cardiac dysfunction." The echocardiography laboratory will evolve into a cardiovascular physiology and pathophysiology laboratory able to decipher the subtle morphologic and physiological characteristics of a heterogeneous group of cardiovascular diseases (82). We will then be able to evolve a new paradigm of what we define as "disease" with "echophysiology" providing insights allowing for more active intervention for prevention strategies. Perhaps in another decade all inscriptions on the Rosetta Stone will be deciphered and we will realize that the translation was not just that of diastology but rather cardiovascular physiology and pathophysiology. Until then...
|
References
|
|---|
1. Kitabatake A, Inoue M, Asao M, et al. Transmitral blood flow reflecting diastolic behavior of the left ventricle in health and disease–a study by pulsed Doppler technique Jpn Circ J 1982;46:92-102.[Medline]2. Nishimura RA, Tajik AJ. Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinician’s Rosetta Stone J Am Coll Cardiol 1997;30:8-18.[Abstract] 3. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction N Engl J Med 2006;355:251-259.[Abstract/Free Full Text] 4. Senni M, Tribouilloy CM, Rodeheffer RJ, et al. Congestive heart failure in the community: a study of all incident cases in Olmsted County, Minnesota, in 1991 Circulation 1998;98:2282-2289.[Abstract/Free Full Text] 5. Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with preserved ejection fraction in a population-based study N Engl J Med 2006;355:260-269.[Abstract/Free Full Text] 6. Abhayaratna WP, Marwick TH, Smith WT, Becker NG. Characteristics of left ventricular diastolic dysfunction in the community: an echocardiographic survey Heart 2006;92:1259-1264.[Abstract/Free Full Text] 7. Redfield MM, Jacobsen SJ, Burnett Jr. JC, Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic JAMA 2003;289:194-202.[Abstract/Free Full Text] 8. Kelly R, Hayward C, Avolio A, O’Rourke M. Noninvasive determination of age-related changes in the human arterial pulse Circulation 1989;80:1652-1659.[Abstract/Free Full Text] 9. Lam CS, Roger VL, Rodeheffer RJ, et al. Cardiac structure and ventricular-vascular function in persons with heart failure and preserved ejection fraction from Olmsted County, Minnesota Circulation 2007;115:1982-1990.[Abstract/Free Full Text] 10. Mitchell GF, Parise H, Benjamin EJ, et al. Changes in arterial stiffness and wave reflection with advancing age in healthy men and women: the Framingham Heart study Hypertension 2004;43:1239-1245.[Abstract/Free Full Text] 11. Redfield MM, Jacobsen SJ, Borlaug BA, Rodeheffer RJ, Kass DA. Age- and gender-related ventricular-vascular stiffening: a community-based study Circulation 2005;112:2254-2262.[Abstract/Free Full Text] 12. Vaitkevicius PV, Fleg JL, Engel JH, et al. Effects of age and aerobic capacity on arterial stiffness in healthy adults Circulation 1993;88:1456-1462.[Abstract/Free Full Text] 13. Diez J, Gonzalez A, Lopez B, Querejeta R. Mechanisms of disease: pathologic structural remodeling is more than adaptive hypertrophy in hypertensive heart disease Nat Clin Pract Cardiovasc Med 2005;2:209-216.[CrossRef][Web of Science][Medline] 14. Martos R, Baugh J, Ledwidge M, et al. Diastolic heart failure: evidence of increased myocardial collagen turnover linked to diastolic dysfunction Circulation 2007;115:888-895.[Abstract/Free Full Text] 15. van Heerebeek L, Borbely A, Niessen HW, et al. Myocardial structure and function differ in systolic and diastolic heart failure Circulation 2006;113:1966-1973.[Abstract/Free Full Text] 16. Borbely A, van der Velden J, Papp Z, et al. Cardiomyocyte stiffness in diastolic heart failure Circulation 2005;111:774-781.[Abstract/Free Full Text] 17. Granzier HL, Labeit S. The giant protein titin: a major player in myocardial mechanics, signaling, and disease Circ Res 2004;94:284-295.[Abstract/Free Full Text] 18. Katz AM, Zile MR. New molecular mechanism in diastolic heart failure Circulation 2006;113:1922-1925.[Free Full Text] 19. Kelly RP, Ting CT, Yang TM, et al. Effective arterial elastance as index of arterial vascular load in humans Circulation 1992;86:513-521.[Abstract/Free Full Text] 20. Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology J Am Soc Echocardiogr 2005;18:1440-1463.[CrossRef][Web of Science][Medline] 21. Lester SJ, Ryan EW, Schiller NB, Foster E. Best method in clinical practice and in research studies to determine left atrial size Am J Cardiol 1999;84:829-832.[CrossRef][Web of Science][Medline] 22. Takemoto Y, Barnes ME, Seward JB, et al. Usefulness of left atrial volume in predicting first congestive heart failure in patients > or = 65 years of age with well-preserved left ventricular systolic function Am J Cardiol 2005;96:832-836.[CrossRef][Web of Science][Medline] 23. Tsang TS, Barnes ME, Gersh BJ, Bailey KR, Seward JB. Left atrial volume as a morphophysiologic expression of left ventricular diastolic dysfunction and relation to cardiovascular risk burden Am J Cardiol 2002;90:1284-1289.[CrossRef][Web of Science][Medline] 24. Tsang TS, Barnes ME, Gersh BJ, et al. Prediction of risk for first age-related cardiovascular events in an elderly population: the incremental value of echocardiography J Am Coll Cardiol 2003;42:1199-1205.[Abstract/Free Full Text] 25. Tsang TS, Gersh BJ, Appleton CP, et al. Left ventricular diastolic dysfunction as a predictor of the first diagnosed nonvalvular atrial fibrillation in 840 elderly men and women J Am Coll Cardiol 2002;40:1636-1644.[Abstract/Free Full Text] 26. Douglas PS. The left atrium: a biomarker of chronic diastolic dysfunction and cardiovascular disease risk J Am Coll Cardiol 2003;42:1206-1207.[Free Full Text] 27. Nagueh SF, Middleton KJ, Kopelen HA, Zoghbi WA, Quinones MA. Doppler tissue imaging: a noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures J Am Coll Cardiol 1997;30:1527-1533.[Abstract] 28. Ommen SR, Nishimura RA, Appleton CP, et al. Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: a comparative simultaneous Doppler-catheterization study Circulation 2000;102:1788-1794.[Abstract/Free Full Text] 29. Oh JK, Tajik J. The return of cardiac time intervals: the Phoenix is rising J Am Coll Cardiol 2003;42:1471-1474.[Free Full Text] 30. Rivas-Gotz C, Khoury DS, Manolios M, Rao L, Kopelen HA, Nagueh SF. Time interval between onset of mitral inflow and onset of early diastolic velocity by tissue Doppler: a novel index of left ventricular relaxation: experimental studies and clinical application J Am Coll Cardiol 2003;42:1463-1470.[Abstract/Free Full Text] 31. Rivas-Gotz C, Manolios M, Thohan V, Nagueh SF. Impact of left ventricular ejection fraction on estimation of left ventricular filling pressures using tissue Doppler and flow propagation velocity Am J Cardiol 2003;91:780-784.[CrossRef][Web of Science][Medline] 32. Wang J, Khoury DS, Thohan V, Torre-Amione G, Nagueh SF. Global diastolic strain rate for the assessment of left ventricular relaxation and filling pressures Circulation 2007;115:1376-1383.[Abstract/Free Full Text] 33. Smiseth OA, Thompson CR, Lohavanichbutr K, et al. The pulmonary venous systolic flow pulse—its origin and relationship to left atrial pressure J Am Coll Cardiol 1999;34:802-809.[Abstract/Free Full Text] 34. Brun P, Tribouilloy C, Duval AM, et al. Left ventricular flow propagation during early filling is related to wall relaxation: a color M-mode Doppler analysis J Am Coll Cardiol 1992;20:420-432.[Abstract] 35. Stugaard M, Brodahl U, Torp H, Ihlen H. Abnormalities of left ventricular filling in patients with coronary artery disease: assessment by colour M-mode Doppler technique Eur Heart J 1994;15:318-327.[Abstract/Free Full Text] 36. Stugaard M, Smiseth OA, Risoe C, Ihlen H. Intraventricular early diastolic velocity profile during acute myocardial ischemia: a color M-mode Doppler echocardiographic study J Am Soc Echocardiogr 1995;8:270-279.[CrossRef][Medline] 37. Firstenberg MS, Levine BD, Garcia MJ, et al. Relationship of echocardiographic indices to pulmonary capillary wedge pressures in healthy volunteers J Am Coll Cardiol 2000;36:1664-1669.[Abstract/Free Full Text] 38. Gonzalez-Vilchez F, Ayuela J, Ares M, Mata NS, Gonzalez AG, Duran RM. Comparison of Doppler echocardiography, color M-mode Doppler, and Doppler tissue imaging for the estimation of pulmonary capillary wedge pressure J Am Soc Echocardiogr 2002;15:1245-1250.[CrossRef][Web of Science][Medline] 39. Ha JW, Oh JK, Ling LH, Nishimura RA, Seward JB, Tajik AJ. Annulus paradoxus: transmitral flow velocity to mitral annular velocity ratio is inversely proportional to pulmonary capillary wedge pressure in patients with constrictive pericarditis Circulation 2001;104:976-978.[Abstract/Free Full Text] 40. Nagueh SF, Rao L, Soto J, Middleton KJ, Khoury DS. Haemodynamic insights into the effects of ischaemia and cycle length on tissue Doppler-derived mitral annulus diastolic velocities Clin Sci (Lond) 2004;106:147-154.[Medline] 41. Ha JW, Oh JK, Pellikka PA, et al. Diastolic stress echocardiography: a novel noninvasive diagnostic test for diastolic dysfunction using supine bicycle exercise Doppler echocardiography J Am Soc Echocardiogr 2005;18:63-68.[CrossRef][Web of Science][Medline] 42. Reuss CS, Moreno CA, Appleton CP, Lester SJ. Doppler tissue imaging during supine and upright exercise in healthy adults J Am Soc Echocardiogr 2005;18:1343-1348.[CrossRef][Web of Science][Medline] 43. Burgess MI, Jenkins C, Sharman JE, Marwick TH. Diastolic stress echocardiography: hemodynamic validation and clinical significance of estimation of ventricular filling pressure with exercise J Am Coll Cardiol 2006;47:1891-1900.[Abstract/Free Full Text] 44. Talreja DR, Nishimura RA, Oh JK. Estimation of left ventricular filling pressure with exercise by Doppler echocardiography in patients with normal systolic function: a simultaneous echocardiographic-cardiac catheterization study J Am Soc Echocardiogr 2007;20:477-479.[CrossRef][Web of Science][Medline] 45. Tajik AJ. Gulf Heart Lecture: new horizons in the management of cardiovascular disease Heart Reviews 2004;5:135-144. 46. Pinamonti B, Zecchin M, Di Lenarda A, Gregori D, Sinagra G, Camerini F. Persistence of restrictive left ventricular filling pattern in dilated cardiomyopathy: an ominous prognostic sign J Am Coll Cardiol 1997;29:604-612.[Abstract] 47. Pozzoli M, Traversi E, Cioffi G, Stenner R, Sanarico M, Tavazzi L. Loading manipulations improve the prognostic value of Doppler evaluation of mitral flow in patients with chronic heart failure Circulation 1997;95:1222-1230.[Abstract/Free Full Text] 48. Stevenson LW, Tillisch JH, Hamilton M, et al. Importance of hemodynamic response to therapy in predicting survival with ejection fraction less than or equal to 20% secondary to ischemic or nonischemic dilated cardiomyopathy Am J Cardiol 1990;66:1348-1354.[CrossRef][Web of Science][Medline] 49. Solomon SD, Janardhanan R, Verma A, et al. Effect of angiotensin receptor blockade and antihypertensive drugs on diastolic function in patients with hypertension and diastolic dysfunction: a randomised trial Lancet 2007;369:2079-2087.[CrossRef][Web of Science][Medline] 50. Arnold JM, Yusuf S, Young J, et al. Prevention of heart failure in patients in the Heart Outcomes Prevention Evaluation (HOPE) study Circulation 2003;107:1284-1290.[Abstract/Free Full Text] 51. Silver MA, Peacock WFt, Diercks DB. Optimizing treatment and outcomes in acute heart failure: beyond initial triage Congest Heart Fail 2006;12:137-145.[CrossRef][Medline] 52. Brilla CG. Aldosterone and myocardial fibrosis in heart failure Herz 2000;25:299-306.[CrossRef][Web of Science][Medline] 53. Brilla CG, Funck RC, Rupp H. Lisinopril-mediated regression of myocardial fibrosis in patients with hypertensive heart disease Circulation 2000;102:1388-1393.[Abstract/Free Full Text] 54. Diez J, Querejeta R, Lopez B, Gonzalez A, Larman M, Martinez Ubago JL. Losartan-dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients Circulation 2002;105:2512-2517.[Abstract/Free Full Text] 55. Kumar A, Meyerrose G, Sood V, Roongsritong C. Diastolic heart failure in the elderly and the potential role of aldosterone antagonists Drugs Aging 2006;23:299-308.[CrossRef][Medline] 56. Peng H, Carretero OA, Vuljaj N, et al. Angiotensin-converting enzyme inhibitors: a new mechanism of action Circulation 2005;112:2436-2445.[Abstract/Free Full Text] 57. Tsang TS, Barnes ME, Abhayaratna WP, et al. Effects of quinapril on left atrial structural remodeling and arterial stiffness Am J Cardiol 2006;97:916-920.[CrossRef][Web of Science][Medline] 58. Yusuf S, Pfeffer MA, 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] 59. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J. The Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF) study Eur Heart J 2006;27:2338-2345.[Abstract/Free Full Text] 60. Carson P, Massie BM, McKelvie R, et al. The Irbesartan in heart failure with PRESERVEd systolic function (I-PRESERVE) trial: rationale and design J Card Fail 2005;11:576-585.[CrossRef][Web of Science][Medline] 61. Ito MK, Talbert RL, Tsimikas S. Statin-associated pleiotropy: possible beneficial effects beyond cholesterol reduction Pharmacotherapy 2006;26:85S-97S.[CrossRef][Web of Science][Medline] 62. Zile MR. Treating diastolic heart failure with statins: "phat" chance for pleiotropic benefits Circulation 2005;112:300-303.[Free Full Text] 63. Goldstein S, Fagerberg B, Hjalmarson A, et al. Metoprolol controlled release/extended release in patients with severe heart failure: analysis of the experience in the MERIT-HF study J Am Coll Cardiol 2001;38:932-938.[Abstract/Free Full Text] 64. Krum H, Roecker EB, Mohacsi P, et al. Effects of initiating carvedilol in patients with severe chronic heart failure: results from the COPERNICUS study JAMA 2003;289:712-718.[Abstract/Free Full Text] 65. Dobre D, van Veldhuisen DJ, Mordenti G, et al. Tolerability and dose-related effects of nebivolol in elderly patients with heart failure: data from the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure (SENIORS) trial Am Heart J 2007;154:109-115.[CrossRef][Medline] 66. Dobre D, van Veldhuisen DJ, DeJongste MJ, et al. Prescription of beta-blockers in patients with advanced heart failure and preserved left ventricular ejection fractionClinical implications and survival. Eur J Heart Fail 2007;9:280-286.[Abstract/Free Full Text] 67. Konrad D, Haney MF, Johansson G, Wanecek M, Weitzberg E, Oldner A. Cardiac effects of endothelin receptor antagonism in endotoxemic pigs Am J Physiol Heart Circ Physiol 2007;293:H988-H996.[Abstract/Free Full Text] 68. MacCarthy PA, Grocott-Mason R, Prendergast BD, Shah AM. Contrasting inotropic effects of endogenous endothelin in the normal and failing human heart: studies with an intracoronary ET(A) receptor antagonist Circulation 2000;101:142-147.[Abstract/Free Full Text] 69. Anand I, McMurray J, Cohn JN, et al. Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the Endothelin A Receptor Antagonist Trial in Heart Failure (EARTH): randomised, double-blind, placebo-controlled trial Lancet 2004;364:347-354.[CrossRef][Web of Science][Medline] 70. Kalra PR, Moon JC, Coats AJ. Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for non-selective endothelin antagonism in heart failure? Int J Cardiol 2002;85:195-197.[CrossRef][Web of Science][Medline] 71. Luscher TF, Enseleit F, Pacher R, et al. Hemodynamic and neurohumoral effects of selective endothelin A (ET(A)) receptor blockade in chronic heart failure: the Heart Failure ET(A) Receptor Blockade Trial (HEAT) Circulation 2002;106:2666-2672.[Abstract/Free Full Text] 72. Zeisberg EM, Tarnavski O, Zeisberg M, et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis Nat Med 2007;13:952-961.[CrossRef][Web of Science][Medline] 73. Nagendran J, Archer SL, Soliman D, et al. Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility Circulation 2007;116:238-248.[Abstract/Free Full Text] 74. Takimoto E, Champion HC, Li M, et al. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy Nat Med 2005;11:214-222.[CrossRef][Web of Science][Medline] 75. Little WC, Zile MR, Kitzman DW, Hundley WG, O’Brien TX, Degroof RC. The effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure J Card Fail 2005;11:191-195.[CrossRef][Web of Science][Medline] 76. Chen J, Liu W, Zhang H, et al. Regional ventricular wall thickening reflects changes in cardiac fiber and sheet structure during contraction: quantification with diffusion tensor MRI Am J Physiol Heart Circ Physiol 2005;289:H1898-H1907.[Abstract/Free Full Text] 77. Nielsen PM, Le Grice IJ, Smaill BH, Hunter PJ. Mathematical model of geometry and fibrous structure of the heart Am J Physiol 1991;260:H1365-H1378.[Web of Science][Medline] 78. Sengupta PP, Khandheria BK, Korinek J, Wang J, Belohlavek M. Biphasic tissue Doppler waveforms during isovolumic phases are associated with asynchronous deformation of subendocardial and subepicardial layers J Appl Physiol 2005;99:1104-1111.[Abstract/Free Full Text] 79. Sengupta PP, Khandheria BK, Korinek J, et al. Apex-to-base dispersion in regional timing of left ventricular shortening and lengthening J Am Coll Cardiol 2006;47:163-172.[Abstract/Free Full Text] 80. Sengupta PP, Korinek J, Belohlavek M, et al. Left ventricular structure and function: basic science for cardiac imaging J Am Coll Cardiol 2006;48:1988-2001.[Abstract/Free Full Text] 81. Sengupta PP, Khandheria BK, Korinek J, et al. Left ventricular isovolumic flow sequence during sinus and paced rhythms: new insights from use of high-resolution Doppler and ultrasonic digital particle imaging velocimetry J Am Coll Cardiol 2007;49:899-908.[Abstract/Free Full Text] 82. Nishimura RA, Jaber W. Understanding "diastolic heart failure": the tip of the iceberg J Am Coll Cardiol 2007;49:695-697.[Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
G. A. Silberman, T.-H. M. Fan, H. Liu, Z. Jiao, H. D. Xiao, J. D. Lovelock, B. M. Boulden, J. Widder, S. Fredd, K. E. Bernstein, et al.
Uncoupled Cardiac Nitric Oxide Synthase Mediates Diastolic Dysfunction
Circulation,
February 2, 2010;
121(4):
519 - 528.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. A ten Brinke, D. Burkhoff, R. J Klautz, C. Tschope, M. J Schalij, J. J Bax, E. E van der Wall, R. A Dion, and P. Steendijk
Single-beat estimation of the left ventricular end-diastolic pressure-volume relationship in patients with heart failure
Heart,
February 1, 2010;
96(3):
213 - 219.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Sam, T.-A. S. Duhaney, K. Sato, R. M. Wilson, K. Ohashi, S. Sono-Romanelli, A. Higuchi, D. S. De Silva, F. Qin, K. Walsh, et al.
Adiponectin Deficiency, Diastolic Dysfunction, and Diastolic Heart Failure
Endocrinology,
January 1, 2010;
151(1):
322 - 331.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-M. Yu, J. Y.-S. Chan, Q. Zhang, G. W.K. Yip, Y.-Y. Lam, A. Chan, D. Burkhoff, P.-W. Lee, and J. W.-H. Fung
Impact of Cardiac Contractility Modulation on Left Ventricular Global and Regional Function and Remodeling
J. Am. Coll. Cardiol. Img.,
December 1, 2009;
2(12):
1341 - 1349.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Moreo, G. Ambrosio, B. De Chiara, M. Pu, T. Tran, F. Mauri, and S. V. Raman
Influence of Myocardial Fibrosis on Left Ventricular Diastolic Function: Noninvasive Assessment by Cardiac Magnetic Resonance and Echo
Circ Cardiovasc Imaging,
November 1, 2009;
2(6):
437 - 443.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. V. Shah, A. A. Chen-Tournoux, M. H. Picard, and J. L. Januzzi
Association between troponin T and impaired left ventricular relaxation in patients with acute decompensated heart failure with preserved systolic function
Eur J Echocardiogr,
August 1, 2009;
10(6):
765 - 768.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Carluccio, P. Biagioli, G. Alunni, A. Murrone, V. Leonelli, P. Pantano, G. Vincenti, C. Giombolini, T. Ragni, G. Reboldi, et al.
Effect of revascularizing viable myocardium on left ventricular diastolic function in patients with ischaemic cardiomyopathy
Eur. Heart J.,
June 2, 2009;
30(12):
1501 - 1509.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. T. Burns, A. La Gerche, D. L. Prior, and A. I. MacIsaac
Left Ventricular Untwisting Is an Important Determinant of Early Diastolic Function
J. Am. Coll. Cardiol. Img.,
June 1, 2009;
2(6):
709 - 716.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. F. Tops, D. W. Den Uijl, V. Delgado, N. A. Marsan, K. Zeppenfeld, E. Holman, E. E. van der Wall, M. J. Schalij, and J. J. Bax
Long-Term Improvement in Left Ventricular Strain After Successful Catheter Ablation for Atrial Fibrillation in Patients With Preserved Left Ventricular Systolic Function
Circ Arrhythm Electrophysiol,
June 1, 2009;
2(3):
249 - 257.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. L. Dini, F. Lattanzi, P. Fontanive, G. M. Rosa, and S. M. De Tommasi
Value of tissue Doppler imaging for risk stratification of patients with chronic systolic heart failure with or without restrictive mitral flow
Eur J Echocardiogr,
June 1, 2009;
10(4):
562 - 566.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y-Y Lam, M J Mullen, M G Kaya, M A Gatzoulis, W Li, and M Y Henein
Left ventricular long axis dysfunction in adults with "corrected" aortic coarctation is related to an older age at intervention and increased aortic stiffness
Heart,
May 1, 2009;
95(9):
733 - 739.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I A Paraskevaidis, F Panou, C Papadopoulos, D Farmakis, J Parissis, I Ikonomidis, A Rigopoulos, E K Iliodromitis, and D Th Kremastinos
Evaluation of left atrial longitudinal function in patients with hypertrophic cardiomyopathy: a tissue Doppler imaging and two-dimensional strain study
Heart,
March 15, 2009;
95(6):
483 - 489.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Kuznetsova, L. Herbots, B. Lopez, Y. Jin, T. Richart, L. Thijs, A. Gonzalez, M.-C. Herregods, R. H. Fagard, J. Diez, et al.
Prevalence of Left Ventricular Diastolic Dysfunction in a General Population
Circ Heart Fail,
March 1, 2009;
2(2):
105 - 112.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. W. Troughton and A. M. Richards
B-type natriuretic peptides and echocardiographic measures of cardiac structure and function.
J. Am. Coll. Cardiol. Img.,
February 1, 2009;
2(2):
216 - 225.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M Saito, H Okayama, K Nishimura, A Ogimoto, T Ohtsuka, K Inoue, G Hiasa, T Sumimoto, J Funada, Y Shigematsu, et al.
Determinants of left ventricular untwisting behaviour in patients with dilated cardiomyopathy: analysis by two-dimensional speckle tracking
Heart,
February 1, 2009;
95(4):
290 - 296.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. N. DeMaria, O. Ben-Yehuda, J. J. Bax, G. K. Feld, B. H. Greenberg, W. Y.W. Lew, J. A.C. Lima, A. S. Maisel, S. M. Narayan, D. J. Sahn, et al.
Highlights of the Year in JACC 2008.
J. Am. Coll. Cardiol.,
January 27, 2009;
53(4):
373 - 398.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Y-M. Wang, M. Wang, C. W-K. Lam, I. H-S. Chan, Y. Zhang, and J. E. Sanderson
Left Ventricular Filling Pressure by Doppler Echocardiography in Patients With End-Stage Renal Disease
Hypertension,
July 1, 2008;
52(1):
107 - 114.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Epidemiology
