The echocardiographic assessment of diastolic function has increasingly gained relevance as a predictor of adverse perioperative outcome.1–3 Before the widespread use of Doppler echocardiography, the presence of different symptoms in 2 patients with a similar degree of systolic dysfunction could not be explained,4 and invasive measurement of left ventricular (LV) end-diastolic pressure (LVEDP) was the only means to conclusively diagnose the presence of diastolic dysfunction. The use of pulse wave Doppler (PWD) to estimate LV relaxation made such an assessment clinically feasible. PWD has furthered our understanding of diastolic function and solved the mystery of discordance between symptoms and ventricular systolic function.4
Echocardiographic assessment of diastolic function has been extensively reviewed in recent American Society of Echocardiography (ASE) guidelines.5 Although not explicitly stated, these guidelines pertain to spontaneously breathing patients undergoing transthoracic echocardiography (TTE).a In this review, we provide a synopsis of the physiology of diastolic function and definitions of diastolic dysfunction, present the various Doppler modalities and how they are potentially affected by the intraoperative environment, and finally, consider how the aforementioned guidelines5 may be applicable in the perioperative setting when using transesophageal echocardiography (TEE).
IMPORTANCE OF PERIOPERATIVE ASSESSMENT OF DIASTOLIC FUNCTION
It is now established that 50% of patients with congestive heart failure (CHF) have normal systolic function,6,7 and the same percentage of patients undergoing cardiac or noncardiac procedures have echocardiographically demonstrable diastolic function abnormalities.8 This may be important, because the presence of preoperative asymptomatic ventricular dysfunction (systolic and diastolic) has been associated with increased 30-day and long-term morbidity and mortality.1 The assessment of diastolic function provides incremental prognostic value over systolic function assessment5,9 and the presence of diastolic dysfunction is highly predictive of adverse events after myocardial infarction.5,10 Echocardiography has been used to diagnose perioperative diastolic dysfunction during cardiac surgery.11–15 However, other than being a predictor of difficult weaning from cardiopulmonary bypass,11,12 the impact of perioperative diastolic dysfunction on short- and long-term postoperative morbidity and mortality in cardiac surgery patients is not conclusively established. Alternatively, in a retrospective review of vascular surgical patients with normal systolic function, patients with a history of CHF were found to have a longer hospital length of stay and a higher readmission rate and postoperative mortality than those without this history (Table 1).16 Although TEE has been used extensively during noncardiac surgery, its use for assessment of perioperative diastolic function is limited.17 In a prospective observational study of patients undergoing vascular surgery,2 the presence of diastolic dysfunction in hospitalized patients was a predictor of increased all-cause morbidity and mortality.18–20 The presence of perioperative diastolic dysfunction, diagnosed with TEE, had a significant association with postoperative CHF and postoperative length of stay after vascular surgery (Table 1).2 Although not conclusively established, it seems that pre- and perioperative diagnosis of diastolic dysfunction may have implications for perioperative anesthetic management and, potentially, postoperative outcome.
PHYSIOLOGY OF DIASTOLIC FUNCTION
Diastole refers to the period of ventricular filling after a contraction (Fig. 1). Diastole is divided into 4 discrete parts: isovolumetric relaxation, rapid filling phase, diastasis, and atrial contraction.4 LV filling during diastole is a complex interplay regulated primarily by the pressure differences between volume and compliance of the left atrium (LA) and LV, and energy-dependent LV relaxation (Fig. 1).21 In addition to LV relaxation, extrinsic factors such as pericardial restraint, ventricular interaction, and intrinsic factors including myocardial stiffness, myocardial tone, chamber geometry, and wall thickness also have a role in LV filling.5,22 The diastolic phase of the cardiac cycle is also dependent on events that occur at the cellular, physiological, and organ level. At the cellular level, diastole begins with the hydrolyzation of adenosine triphosphate and unlinking of actin and myosin cross-linkages,23 followed by a reduction in sarcoplasmic calcium concentration and its separation from troponin (Fig. 2). Physiologically, ventricular relaxation at the onset of diastole as defined by the rate of decline of intracavitary pressure (−dP/dt) actually begins in the later portion of clinical systole, while the mitral valve is still closed (Fig. 1).4 Ventricular relaxation is an energy-dependent process, physiologically commencing during systole, continuing after mitral valve opening (clinical diastole) during rapid LV filling, lasting for the first third of this early filling phase and normally accounts for almost 70% of LV filling (Fig. 1). Hence, during the early LV diastole, in addition to the LA-LV gradient, the effectiveness of LV suction also determines the adequacy of filling. The LV continues to fill until closure of the mitral valve. The last part of the filling phase is associated with atrial contraction which normally contributes almost 30% of the LV filling. Factors that delay calcium removal impair actin-myosin cross-bridge detachment and therefore slow myocardial relaxation.22 Multiple energy-dependent enzymatic pathways maintain calcium homeostasis in the cytosol.23–28
DIASTOLIC DYSFUNCTION AND HEART FAILURE
In the natural course of myocardial dysfunction caused by ischemia or hypertension, relaxation (early diastolic) abnormalities often precede systolic dysfunction. This results in impairment of early/rapid LV filling and a compensatory increase in late LV filling.4 The LA contribution is determined by LA preload and contractility as well as the “effective LV compliance.”4,29–32 With disease progression, abnormalities of relaxation eventually progress to reduced compliance and increase of filling pressures in both the LA and LV, i.e., mean pulmonary capillary wedge pressure >12 mm Hg and LVEDP >16 mm Hg.33 The invasively measured peak negative change in LV pressure during diastole (−dP/dt) and the time constant of relaxation (τ) are considered the “gold standard” measures of LV relaxation,34,35 against which the accuracy of Doppler-derived variables of diastolic function should be established.
Although used interchangeably, diastolic dysfunction and diastolic heart failure are actually 2 different pathophysiological conditions. The use of the term “diastolic dysfunction” implies an echocardiographically demonstrated abnormality of LV filling, i.e., impaired relaxation and/or reduced compliance, which results in increased LVEDP, whereas diastolic heart failure is a clinical term, which is the symptomatic manifestation (shortness of breath and exercise intolerance) of the underlying filling abnormality, i.e., an increased LVEDP, in the presence of normal LV systolic function.36 The time course of progression from diastolic dysfunction to diastolic heart failure can be variable. For example, in patients with hypertension and LV hypertrophy, impaired relaxation may remain the predominant abnormality for a long time without any increase in LVEDP.37
ECHOCARDIOGRAPHIC ASSESSMENT OF DIASTOLIC FUNCTION: CHALLENGES AND PITFALLS
Assessment of diastolic function based on Doppler findings acquired with TTE may not be entirely applicable to TEE techniques. Because of its noninvasive nature, TTE has been extensively used over the decades in epidemiological studies in subjects with normal and abnormal filling patterns. Hence, the reference values for Doppler indices of LV diastolic function are well established with this technique (Table 2).5 The invasive nature of TEE and variable intraoperative hemodynamic state has precluded similar efforts. The majority of echocardiographic studies of the assessment of diastolic function have been conducted in outpatient cardiology clinics in patients breathing spontaneously in the lateral decubitus position.30 However, the filling variables of LA and LV significantly change with alterations in posture from supine to upright and left to right lateral decubitus position.38–40 In contrast, echocardiographic studies under general anesthesia (GA) are performed with TEE under varying hemodynamic states and in patients in the supine position who are receiving positive pressure ventilation and are under the effects of anesthetic drugs.
CLASSIFICATION OF PERIOPERATIVE DIASTOLIC FUNCTION
The classification of diastolic dysfunction has evolved from the initial, transmitral flow (TMF) examination with a PWD-based explanation of LA and LV filling and its abnormalities, to the most current guidelines, which have incorporated PWD and more sophisticated techniques (Fig. 3).4,5,29,30,41–46 However, such classification schemes4,29,30,44,47 for the assessment of diastolic dysfunction are suited for categorization of larger patient populations and assess response to therapy (epidemiological studies).5 For the individual patient, it is recommended to use a customized approach to answer specific mechanistic questions, e.g., diagnosis of impaired relaxation and/or a coexistent reduced compliance abnormality.5
The clinical application of these guidelines has also demonstrated the limitations of such classification schemes. In one study, one of the Doppler criteria, pulmonary venous PWD profile, could not be obtained in 28% of patients undergoing elective TTE examinations,48 and in the study by Redfield et al.44 (n = >2000), in which only 2 of the 4 Doppler criteria were required for classification, 12% of patients could not be accurately classified and were termed “indeterminate patterns.” Intraoperative rigid application of the most recent ASE guidelines has also demonstrated their limitation in classifying perioperative diastolic dysfunction.3
Factors such as ventricular interdependence,49 effects of positive pressure ventilation,50,51 and even acute alterations in coronary blood flow by altering the vascular turgor (i.e., the “erectile effect”),52 are not accounted for in these classifications, but affect ventricular compliance.4,29,30,44,47 Changes in LV filling variables with induction of GA are also associated with significant changes in LA and LV diameters implying contribution of the loading conditions to these observed effects.53
The intraoperative hemodynamic state is very variable. Consequently, an isolated Doppler measurement should be considered only a “snapshot” of a continuous process. Even minor alterations in the Doppler measurements can lead to a patient being classified into a different grade/stage of diastolic dysfunction in the same clinical setting. Unlike the previous recommendations,4,29,30,44 the current ASE guidelines for echocardiographic assessment of diastolic function have acknowledged the limitations of rigid application of the conventional Doppler indices.4,30,54–60 Therefore, the most recent guidelines no longer recommend the acquisition of E and A waves of the TMF with PWD as the initial step in the decision tree of grading diastolic dysfunction (Fig. 4).5
The techniques for acquisition and interpretation of specific Doppler abnormalities have already been extensively reviewed.5,54 In the following section, the specific steps of obtaining satisfactory Doppler profiles for diastolic function evaluation using TEE are discussed. Echocardiographic evaluation of diastolic function is best accomplished when it is incorporated within a standardized echocardiographic examination, which should also include a comprehensive evaluation of LV systolic function.56,61 Before starting the Doppler examination, it is essential to ensure the most optimal parallel Doppler alignment during interrogation to minimize the degree of underestimation of peak velocities and gradients. Alignment is usually most optimal when using the midesophageal (ME) 4-chamber and ME long-axis views for the majority of the Doppler indices. Echocardiographic evaluation of perioperative diastolic dysfunction with TEE should include a focused and precise examination using a combination of PWD (transmitral and pulmonary venous flows), transmitral color M-mode, and Doppler tissue imaging (DTI) (Fig. 3).
The traditional assessment of LV filling has been based on assessment of the pattern of diastolic blood flow through the mitral valve (LV inflow) using PWD.43 Flow across the mitral valve during the relaxation phase is determined by the LA-LV pressure gradient and the effectiveness of the suction properties of the LV (Fig. 5).60,62 Kitabatake et al.,43 in 1982, described Doppler interrogation of mitral inflow during diastole as a reflection of the global LV relaxation properties.57,58,60,63,64 Abnormalities of the “active relaxation phase” of diastole are generally the earliest manifestations of diastolic dysfunction. The relaxation abnormalities present echocardiographically as changes in E wave peak velocity and deceleration time (DT) initially, and then further changes with disease progression. Based on this progression of abnormalities (impaired relaxation to reduced compliance), distinct echocardiographic patterns, including normal, impaired relaxation, pseudonormal, and restrictive patterns (Figs. 5–8) of LV filling, were described.41,65–71 Mathematical modeling has demonstrated that LA stiffness remains constant during early LV relaxation and DT is proportional to the inverse square root of LV stiffness.31,72–74 Consequently, when there is advanced diastolic dysfunction with reduced compliance, DT is shortened again in the more advanced stage of diastolic dysfunction (Fig. 8). Therefore, in addition to being prolonged during the impaired relaxation phase, DT is an important variable that reliably predicts LV compliance in the more advanced stages of diastolic dysfunction.75
Placement of a color flow Doppler (CFD) sector on the LV inflow can be helpful in aligning the Doppler beam with the direction of the blood flow, which is generally directed toward the lateral wall.61 All measurements should be made during apnea to minimize the hemodynamic changes and movement of the PWD sample volume during controlled mechanical ventilation. For LV inflow assessment, a sample volume of 1 to 3 mm is placed between the mitral tips during diastole with the sweep speed set at 50 to 100 mm/s (Fig. 5). Measurements should include peak E and A velocity, the E/A ratio, DT, and A-wave duration (Adur). For measurement of Adur, it is best to move the cursor to the mitral annular plane with a simultaneous reduction in wall filters (Fig. 5).61 The actual measurement of volumetric flow (continuity equation) does not add any further information.30
Transmitral PWD has been the cornerstone of classification schemes for diastolic dysfunction. Because of its load dependence, TMF is of value only when considered in combination with other Doppler variables, such as the pulmonary venous inflow (PVF), TMF propagation velocity (Vp), and DTI, which are discussed in later sections.
Pulmonary Venous Inflow
The LA acts as a conduit during early diastole, as a contractile chamber during late diastole, and as a reservoir during systole when the mitral valve is closed. During diastole, the LV, LA, and pulmonary veins remain in continuity with a shared pressure gradient.76–83 Hence, the assessment of diastolic function by transmitral PWD can be further refined with incorporation of measurements from the pulmonary venous PWD spectral recording.79,80,84–87 The PVF pattern has shown good correlation with LV filling pressures (LVFPs) in patients with sinus rhythm as well as heart block, but is generally less reliable in patients with significant mitral regurgitation, stenosis, or prosthetic mitral valves and annuloplasty rings.82,88
To acquire a PVF PWD spectral display, a 2- to 3-mm sample volume is placed at 1 cm depth usually in the left upper pulmonary vein visualized in an ME view (Fig. 9). Wall filters must be low to optimize the acquisition of the atrial reversal (Ar) wave. Although satisfactory acquisition of the Ar wave has been reported in almost 80% of ambulatory patients, it is more difficult in critical care settings.89,90
During a PWD examination of the PVF, peak S and D waves, the S/D ratio, and Ar peak velocity and duration should be measured (Fig. 10). Technical difficulties in obtaining the PVF wave profiles, their load dependence, presence of LA wall artifacts, and the effects of arrhythmias on atrial contraction are the major limiting factors.30,91 Further extrapolation of the PVF profile includes S/D ratio calculation and comparison of the duration of the Ar wave with transmitral Adur for LVEDP estimation (Ar duration will be longer than Adur because of decreased antegrade flow caused by reduced LA compliance with LA contraction) (Fig. 10).
Transmitral Color M-Mode–Derived Early Propagation Velocity
Early diastolic LV filling is dependent on the development of progressively negative intraventricular pressure gradients, which create a wavefront of propagation from the LV base to the apex.92–96 This wavefront can be visually appreciated with CFD interrogation of the LV cavity during diastole, when blood is seen entering along the lateral LV walls (Fig. 11). Transmitral Vp is a velocity profile derived by simultaneous use of CFD and M-mode (Fig. 11). Similar to the transmitral E wave, Vp reflects the effectiveness of the LV “suction” during early diastole. Vp is a more valid assessment of the LV relaxation properties compared with TMF, which is a point measurement at the tips of the mitral leaflets.
A CFD sector using a Nyquist limit <40 cm/s is placed on the LV cavity, directed toward the lateral wall, to develop a flow profile. An M-mode cursor is then positioned through the center of the flow profile (Fig. 11). Multiple methods of measuring Vp have been described with varying degrees of intra- and interobserver variability.92,97,98 The method described by Garcia et al., in which the slope of the first aliasing velocity (the outermost velocity) is measured, is considered the most reliable and reproducible method.97,99 A Vp value of <0.50 m/s is consistent with impaired relaxation.5
The feasibility of the intraoperative use of Vp for assessment of diastolic function has been demonstrated.2,12,14,90 Because Vp can be easily measured in a single step, it is an attractive option for intraoperative assessment of LV relaxation. However, sometimes in addition to the diastolic suction force, multiple other factors, e.g., changes in LV geometry, contractile dyssynchrony, and tissue viscoelastic forces also have a role in creating these LV inflow vortices.100–102 However, it may not be possible to measure Vp because the slope of flow propagation is sometimes curvilinear and does not “travel” a sufficient distance (<4 cm) into the LV cavity or is difficult to appreciate.99 Additionally, an abnormal Vp merely diagnoses the presence of abnormal relaxation, and not necessarily its severity. Therefore, an abnormal Vp may not differentiate among the various stages of abnormal diastolic function, and a decreasing Vp value has not been associated with progressive worsening of diastolic function. Despite these limitations, Vp remains a valuable tool in the determination of development of intraventricular pressure gradients. However, Vp has been shown to increase with increasing preload and can be normal despite increased filling pressures in patients with a normal ejection fraction (EF) and LV volume.99
Doppler Tissue Imaging
Recent advancements in echocardiographic equipment, including the ability to record “high amplitude and low velocity” signals, have made it possible to measure tissue velocities and motion. In ultrasound systems with installed DTI presets, a 5- to 10-mm sample volume is placed in the lateral or medial mitral annulus to obtain a PWD spectral pattern (Fig. 3). A typical DTI signal consists of the following 3 main waves: early (E′) and late (A′) diastolic, and a systolic (S′) (Fig. 12).61 Similar to the TMF E wave, the E′ wave peak velocity has been associated with the relaxation constant (τ). Although both TMF E and the DTI E′ waves represent early diastolic filling, under normal conditions, the DTI E′ wave precedes the TMF E wave because myocardial relaxation precedes opening of the mitral valve and LV inflow. Similarly, the DTI A′ wave is associated with late LV inflow and atrial contraction. Myocardial motion at the atrioventricular (AV) interface has also been shown to correlate with LVFP.103–106
DTI should be performed in the ME 4-chamber view to obtain a parallel Doppler alignment. Most modern echocardiographic systems have manufacturer-installed presets to obtain DTI signals. During acquisition, the velocity scale should be set to <20 cm/s. Acquisition should be performed at end-expiration, and at a sweep speed of 50 to 100 mm/s. An average of >3 beats of the lateral mitral annular DTI should be measured. Because systolic function also has a role in mitral annular excursion, it is recommended that different E′ cutoff values be used for patients with a depressed EF. In cases of regional LV dysfunction and wall motion abnormalities, it is important to average velocity measurements from both septal and lateral mitral annuli.5,107
The normal value of the E′ wave is age dependent and determined by the site of measurement (i.e., lateral versus medial mitral annulus) (Table 2).5 For diastolic function interrogation, a reduced E′ velocity for age is considered diagnostic of abnormal LV relaxation. Further measurements of the E′ wave (acceleration/deceleration rate) do not add any incremental information.108 However, calculation of the time interval between the QRS wave and onset of the E′ wave can possibly provide incremental information about diastolic function generally and relaxation abnormalities in particular.107,109 An E′/A′ ratio of >1 during a Valsalva maneuver has also been used to establish normalcy of diastolic function.105,110 As opposed to pseudonormalization of TMF, an abnormal E′/A′ ratio (<1) does not revert to normal (>1) when the LA pressure is increased.105 In addition, the average E′ velocity may not accurately represent global LV diastolic function in the presence of basal lateral and septal wall motion abnormalities, after mitral valve replacement and surgical septal myectomy.61 Furthermore, similar to Vp, the E′ wave represents only the relaxation (early) phase of diastole and does not provide any information about LV compliance.
With a primary relaxation abnormality, there is a delayed equilibration of pressure between LA and LV, which results in less filling in early diastole and more filling during atrial contraction. Therefore, in a typical impaired relaxation pattern, which is considered the initial stage of diastolic dysfunction, there is a decrease in E wave velocity, prolongation of DT, and a compensatory increase in A wave velocity, resulting in an E/A ratio <1 (DT >220 milliseconds) (Fig. 6). A typical impaired relaxation pattern is also characterized by a PVF pattern in which the S/D ratio remains <1 expressing decreased early diastolic flow, and a Vp <50 cm/s, while E′/A′ will be <1 and the onset of E′ will be delayed compared with the E wave. Persistence of relaxation abnormalities due to continued myocardial dysfunction causes LV remodeling and leads to reduced LV compliance, which manifests itself as an increase of LVEDP and an increase in LA pressure. The increased LA pressure overcomes the resistance to LV early filling because of impaired relaxation, and results in increased filling during early diastole and rapid equalization of pressure between the LA and LV because of reduced compliance characterized by an increased E velocity and shortened DT. As a result, there is limited filling during atrial contraction because of decreased LV compliance (Fig. 8). Also, PVF will show an S/D ratio >1, implying increased LA pressure and decreased flow from the pulmonary veins into an incompletely emptied LA during diastole. Vp will be <50 cm/s and DTI will reveal an E′/A′ <1 (Ar duration will be longer than Adur because of decreased antegrade flow due to reduced LA compliance with LA contraction). This is described as a restrictive filling pattern, the final stage of diastolic dysfunction (Fig. 8). An intermediate pattern can sometimes be appreciated during progression from impaired relaxation to the restrictive phase. Because it resembles the normal pattern, it is called a “pseudonormal” pattern and is difficult to appreciate, mostly because of load dependence of the Doppler variables. Because of impaired filling during early diastole, blood backs up in the LA and leads to an increase of the LA pressure. In this intermediate stage, the LA pressure, not ventricular relaxation, is the driving force for early LV filling, and compliance can be normal in this stage (Fig. 13). This indeterminate pattern often precedes the appearance of the restrictive phase. Echocardiographic representation of this stage is seen as a “recovered” E/A ratio (E/A >1) and a shortened DT (Fig. 13), which approaches a normal value. Therefore, in pseudonormalization, despite the underlying impaired relaxation, the transmitral PWD velocities change to a “normal-appearing” profile (Fig. 7).
Hence, the challenge during echocardiographic evaluation is to differentiate pseudonormal (volume compensation with impaired relaxation) from a true normal filling pattern. Because the underlying relaxation abnormality coexists with a compensatory increase of LA pressure to preserve early LV filling, maneuvers that reduce LA pressure including the Valsalva maneuver have been advocated to unmask this compensation and uncover the underlying impaired relaxation. A reduction in LA pressure results in a decreased LA-LV gradient during early diastole, thus negating the effect of increased LA pressure as the main driving force for LV filling. Typically, during such a maneuver, a normal-appearing pattern reverses to an impaired relaxation pattern (E/A <1) and a prolongation of DT (Fig. 7).42,45,46 Performance of the Valsalva maneuver in a “true” normal TMF pattern would result in an equal reduction in the E and A wave magnitude with the E/A ratio remaining >1. Although frequently used, there is no standardized method of performing the Valsalva maneuver. An increase of intrathoracic pressure to 40 mm Hg for at least 10 seconds with simultaneous recording of transmitral PWD has been used in various studies.111,112 During controlled mechanical ventilation, the Valsalva maneuver can be performed by discontinuing the controlled mode and using the “pop-off” valve of the anesthesia machine to generate the required peak inspiratory pressure. The accuracy of Valsalva as well as other preload reduction maneuvers (nitroglycerin administration, which acts by reducing cardiac preload) in conclusively differentiating a normal from pseudonormal pattern of LV filling has been questioned.112 Particularly during an intraoperative TEE examination, the inability to maintain parallel Doppler alignment during the Valsalva maneuver, the associated hemodynamic instability (hypotension) and availability of Doppler indices, which are less likely to demonstrate pseudonormalization, e.g., Vp and DTI, limit the utility of information gained from routine performance of the Valsalva maneuver.
INFLUENCE OF HEMODYNAMICS ON DOPPLER ASSESSMENT OF DIASTOLIC FUNCTION
The dependence of PWD variables on loading conditions was established early on.54,57,113 Different LV filling patterns could be observed in the same patient, because of varying loading conditions, only hours apart.4,57,58,60,114–116 For example, because of the curvilinear relationship of the pressure-volume relationship, sudden preload augmentation without alteration in compliance results in a higher pressure (Fig. 14). A similar and indistinguishable effect can also be observed with increased pericardial restraint associated with pericardial effusion or constrictive pericarditis (Fig. 14).4 Both of the aforementioned scenarios would lead to an increased LA pressure resulting in an increase in the peak E velocity and shortened DT,4 causing a pseudonormal pattern.
It has been demonstrated in animal experiments that a moderate increase in preload does not affect relaxation.117 Although the exact mechanism is unknown, changes in sarcolemmal calcium ion metabolism with preload alterations have been demonstrated on a cellular level.118 Clinically, TMF (E and A waves and DT), PVF (S and D), and DTI E′ waves show changes with alteration of the loading conditions.4,5,29 Because patients undergoing hemodialysis undergo acute reduction in preload with dialysis, they are a unique cohort for such an assessment.119–124 Such studies have, however, generated conflicting results, with some showing independence,119–125 and others demonstrating dependence on preload changes.126–129 It is quite possible that the conflicting results are attributable to the differences in the duration of dialysis and volume of fluid removed during dialysis in these patients.
Whether Vp is load independent has not been conclusively established.5,29,96,98,99,130–133 Even though the E′ peak velocity has also shown to be preload dependent when diastolic function is normal, in the presence of diastolic dysfunction, both Vp and E′ become preload independent and remain reduced despite increasing preload.105 However, in a study in which preload was reduced during hemodialysis, DTI values consistently varied with the magnitude of preload reduction.126,134,135 However, these findings were dependent on the site of DTI measurement with the lateral mitral annular E′ velocity being more resistant to acute reduction in preload than the medial annulus E′ peak velocity.134,136 It is important to consider that a single DTI E′ value is a regional value only, and unless averaged from as many basal sites as possible, it should not be used independently in the diagnosis of diastolic dysfunction.
The response of myocardial relaxation to increasing afterload depends on the LV contractile reserve.137–141 The magnitude, duration, and timing of increased afterload also affect diastolic function.21,142 If LV systolic function is normal, an afterload increase shortens DT, implying improved relaxation and a more rapid, compensatory pressure equilibration between the LA and LV.21 Alternatively, if systolic function is depressed, severe afterload increase in the latter third of diastole prolongs DT, implying impairment in active relaxation143 and is a decompensatory response.142 “Afterload reserve” determines the ability of the LV to respond to increases in afterload without changes in end-systolic volume. Reduced afterload reserve has been shown in the LV with systolic dysfunction143–147 and increases of afterload in such a situation can cause marked deterioration of diastolic function.137,148 A decrease in the rate of LV pressure decline and incomplete relaxation during diastole eventually lead to an increase of pressure in the LA and pulmonary vasculature.149,150
Clinically, the echocardiographic changes in LV diastolic function have been investigated in patients undergoing open abdominal aortic aneurysm surgery.90,151–153 In a study using intraoperative TEE and a pulmonary artery catheter, it was demonstrated that application of an aortic cross-clamp in the infrarenal position led to increased pulmonary artery occlusion pressure without a concomitant change in LV end-diastolic area. Because of the lack of Doppler availability, the authors attributed this observation to reduced compliance of the LV after cross-clamp application with a higher intracavitary pressure for the same volume and, thus, a change in diastolic filling without a concomitant change in systolic function.151 Minor changes in diastolic function with abdominal and thoracoabdominal aortic cross-clamp application were reported in TMF with PWD, probably reflecting changes with loading conditions.152,154 However, when Vp with a cutoff value of <0.45 m/s was used for a similar assessment, an abdominal aortic cross-clamp application was associated with a worsening of LV relaxation, which returned to baseline value after unclamping of the aorta.90 In this study,90 traditional PWD measures (including TMF and PVF) of diastolic function were also used for comparison with Vp but were not as conclusive.
TMF variables are affected by heart rate and rhythm.5,155 Sinus tachycardia and first-degree AV block can result in fusion of E and A waves,5 making it difficult to distinguish E from A and measure DT. Similarly, in atrial flutter, there are usually no A waves.5,155 Different AV blocks (3:1, 4:1) may show multiple atrial filling waves and occasionally diastolic mitral regurgitation during the nonconducted beats.156 During atrial fibrillation, there are no A waves on the spectral PWD, but the DT correlates with the LVFP if systolic function is impaired.155,157 Similarly, peak E′ velocity can be reliably used for assessment of relaxation abnormalities in patients with atrial fibrillation using the same cutoff values as for patients with sinus rhythm.155,157
Heart rate alterations have not been shown to affect the Vp slope.100 Because direct atrial pacing does not seem to change the Vp slope, the positive correlation between Vp and heart rate observed in animal studies is attributed to the pharmacological β-adrenergic stimulation used in these studies.98,130
The effects of acute ischemia on diastolic function depend on the specific mechanism.158 Myocardial ischemia due to acute or chronic reduction of blood supply leads to the onset of systolic dysfunction with diastolic function remaining relatively preserved.159,160 Alternatively, myocardial ischemia due to increased demand causes diastolic dysfunction with little or no effect on systolic function.160–164 The exact cause of these different responses is unknown.160 Perioperatively, myocardial ischemia occurs because of increased demand, and hence changes of diastolic function associated with impaired relaxation are more likely to occur during such an episode. More recently, DTI has been investigated as a sensitive marker of myocardial ischemia, with E′ velocities decreasing acutely with the onset of ischemia.165,166 In an animal model of myocardial ischemia, reduction of E′ peak velocity and E′/A′ ratio occurred before the appearance of wall motion abnormalities,167,168 in proportion to the reduction in blood supply,167,168 making it a promising early echocardiographic marker of ischemia. The reduction in E′/A′ ratio is easy to appreciate visually, and does not require an absolute parallel Doppler alignment. An E′/A′ ratio <1 is usually measured in a majority of hypokinetic and akinetic segments.105
When evaluating diastolic function, measurements should be performed multiple times during periods of apnea and relative hemodynamic stability to minimize the effects of hemodynamic alterations (preload, afterload, heart rate, and contractility). In light of the recent ASE guidelines, the Doppler variables used to interrogate LV diastolic function should be used to assign a severity grade and define and diagnose the specific abnormality, e.g., abnormal relaxation and/or decreased compliance. It is important to remember that the diastolic function assessment must be performed within the context of the recommendations of the current ASE guidelines.
The changes in appearance of Doppler modalities in an impaired relaxation abnormality are determined by the rapidity of equilibration of LA and LV pressures. When this is delayed, it manifests itself as a reduced E velocity, prolonged DT, decreased E′, and reduced Vp. These changes can be masked with increased filling pressures, particularly if systolic function is intact. Because the exact effect of alterations in loading conditions on Doppler assessment of LV filling is unknown, preferably a single Doppler variable should not be used to interrogate diastolic function. The ASE guidelines recommend the assessment of relaxation abnormalities using Doppler modalities, which assess LV relaxation directly or indirectly. Of the “direct” measures of relaxation, isovolumetric relaxation time (IVRT) can be easily measured in the operating room (Fig. 15); however, as an independent measure, it has limited accuracy as a result of multiple factors. For practical application in the operating room, the modalities that assess LV relaxation indirectly are easier to measure and compute (Fig. 16). Particularly, Vp has been shown to be a more reliable index of LV relaxation in patients with depressed EF and those with dilated cardiomyopathy. Similarly, most patients with lateral E′ velocity <8.5 cm/s have impaired relaxation abnormalities.
Assessment of Compliance
Invasive calculation of the LV chamber stiffness constant (i.e., pressure-volume relationship) is considered the gold standard of LV compliance. The compliance constant can be estimated indirectly using echocardiography, but is of limited accuracy, particularly in patients with advanced diastolic dysfunction. Reduced LV compliance is associated with a faster pressure equilibration between the LA and LV, which leads to a shortened DT, an important surrogate measure of reduced compliance (Fig. 18). The transmitral A wave represents the LA-LV pressure gradient during late diastole, and is affected by the LA contractile function as well as LV compliance. Similarly, A-wave transit time, which is the time it takes for the atrial contraction wave to propagate to the LV apex, can be considered a surrogate measure of LV stiffness and has shown good correlation with simultaneously measured invasive LV pressures.169,170 However, the applicability of this particular Doppler modality for use in the operating room as a sole measure of LV compliance remains to be established.
Echocardiographic assessment of diastolic function is performed to specifically assess relaxation or compliance, but has to be performed in the context of assigning a severity grade based on the recommended guidelines (Fig. 4). According to the recommendations, it should start with DTI of the mitral annulus and then progress in a stepwise logical approach incorporating information obtained from the TMF, PVF, and, if required, subsequent performance of a Valsalva maneuver (Fig. 7). Using the ratios of various peak velocities obtained with Doppler, LVFP can be estimated and hence help in further refining the assessment of diastolic function.
Estimation of LVFP
The ASE guidelines suggest that Doppler variables can also be used for estimation of LVFP. However, the degree of systolic function should be taken into consideration when making such estimations (Figs. 17 and 18). For patients with a depressed EF, such an assessment should start with a PWD of the TMF. A peak E velocity <50 cm/s or E/A ratio <1 implies a normal LA pressure. An E/A ratio >2 or a DT <160 milliseconds is considered diagnostic of increased LA pressure (Fig. 17). For TMF, E/A patterns between the 2 extremes need further assessment using DTI (E′), PVF (S/D ratio, Adur, and Ar duration comparison), Vp, and sometimes changes in E/A ratio with the Valsalva maneuver. In the presence of systolic dysfunction, preload does not affect E′ velocity; hence, in patients with impaired relaxation, the ratio of E/E′ can be used to correct for the effect of increased preload on the E wave and prediction of filling pressures. Similarly, E/Vp ratio has also been shown to correlate with increased LA pressure, and a longer Ar duration than the Adur implies increased filling pressure. Although recommended by the ASE guidelines, LA volume cannot be calculated or measured reliably using intraoperative TEE.
Specifically, in patients with depressed systolic function (EF <50%), E/Vp >2.5,97,107 E/E′ >15,171 and Ar-Adur >30 milliseconds (Figs. 17 and 18) are indicative of increased filling pressures.5 When LA pressure is elevated, the transmitral E wave occurs before the mitral annular E′ wave, and the time interval between the onset of E and E′ wave (TE–E′) is prolonged. An IVRT/TE–E′ ratio of <2 is dependent on τ and is a sensitive indicator of increased LV pressures.172
Estimation of LVFPs in patients with preserved systolic function is approached differently. It should be initiated with calculation of an E/E′ ratio. An E/E′ ratio >13 indicates increased LVFP (Fig. 18).103,104,107,171,173–176 An E/E′ ratio of <8 implies normal LVFPs and when the ratio is between 9 and 13, other Doppler variables may be used to estimate LVFP.103 It is recommended to use the averaged mitral annulus–derived E/E′ ratio calculation for LVFPs.107,173 An Ar-Adur >30 milliseconds and an IVRT/TE–E′ ratio of <2 are also indicative of increased LVFPs.5
Because an E/E′ ratio of 9 to 13 can be associated with a normal or an increased LA pressure, it is important to integrate information from multiple Doppler modalities and clinical information. For example, pulmonary artery catheter–derived systolic pressure can be used to diagnose increased LA pressure when E/E′ is 9 to 13 in the presence of depressed or normal systolic function. The ratio E/Vp can be more reliably used to predict LVFP in patients with depressed systolic function.5
LA Size and Diastolic Dysfunction
Recently, LA size/volume measured with TTE has been found to be an indicator for the severity/chronicity of diastolic dysfunction, because during diastole the LA gets exposed to the elevated LVEDP. Clinically, LA size can be considered the “barometer” of the severity of diastolic dysfunction.177 It is recommended that the size of the LA should be measured by Simpson's biplane method and indexed to the body surface area.177–179 The graded LA volume is a simple measure and can be clinically used as a predictor of adverse cardiovascular complications including myocardial infarction and stroke.180–184 However, it is important to know that LA size cannot be accurately measured with TEE because of atrial foreshortening. Hence, the relevance of LA size in the perioperative assessment of diastolic dysfunction is limited to the knowledge of its preoperative size and interpretation of perioperative Doppler indices in the context of this information.
ANESTHETIC DRUGS AND DIASTOLIC FUNCTION
Since the early pioneering work performed by Pagel et al.49,160,185–191 to assess the effects of anesthetic drugs on LV diastolic function, there has been little or no effort by anesthesiologists to use Doppler to investigate the same effects (Table 3). Incorporation of Doppler interrogation of ventricular filling characteristics has the potential to transform the currently performed “anatomical” intraoperative TEE examination to an “anatomical and physiological” examination. In the following section, a synopsis of the available literature on the effects of anesthetic drugs on LV diastolic characteristics (echocardiographic and invasively measured) is presented.
The effect of anesthetic drugs on LV relaxation is not well known. Animal studies with invasive manometric catheters in the 1990s have demonstrated that halothane, isoflurane, enflurane, and desflurane prolong the IVRT,187,192,193 leading to impaired early LV filling.188,190 Echocardiographic studies in rats have demonstrated significant changes in TMF of LV filling during induction of GA with inhaled drugs.194 Among the inhaled anesthetics, only halothane has been shown to reduce LV compliance in an animal model.187,195 Impaired LV relaxation caused by inhaled anesthetics is possibly mediated by altered sarcoplasmic calcium metabolism because it is possible to reverse it with exogenous calcium administration in animal experiments.186,188 In the aforementioned studies, LV and aortic pressures were measured invasively with micromanometric catheters.187,192,193,196–198 Whether inhaled drugs have similar effects on patients with preexisting diastolic dysfunction is unknown. Interestingly, desflurane and isoflurane have been shown to preserve regional systolic function and improve diastolic function in ischemic dogs, an effect possibly mediated by a reduced LV preload.185
More recently, investigators using Doppler echocardiography and a standardized GA protocol in patients without any preexisting cardiac disease demonstrated that halothane and sevoflurane did not cause prolongation of the IVRT199 and the impairment of relaxation was not considered of significant magnitude to be clinically relevant.199 In patients with preexisting diastolic dysfunction, however, administration of sevoflurane caused a slight improvement in early LV relaxation assessed with E′ velocity.200 The results seem to contradict the earlier reported adverse effects of inhaled anesthetics on LV relaxation.187,192,193,196–198 Differences in study population (animals versus humans), medication doses, and methodology (Doppler versus invasive pressure measurements) could possibly explain these contradictory results.199,200 Similar effects were also observed in one human study in which isoflurane did not exacerbate preexistent diastolic dysfunction201 and had no lusitropic effects, i.e., improving relaxation in an animal study using invasive means.202 In 2 separate animal studies, the addition of nitrous oxide and desflurane was shown to increase chamber and myocardial stiffness.203,204 Inhaled anesthetic drugs also exert profound effects on the contractile, reservoir, and conduit function of the LA and also significantly impact LV filling as assessed by TMF with E and A waves.189,205 This loss of LA contractile function was also observed in human atrial tissue in an in vitro study.206
There are only a few studies that have investigated the effects of IV drugs on perioperative diastolic function. Barbiturates and ketamine exert similar effects by inhibition of sarcolemmal transport of calcium ions, and ketamine has also been additionally shown to reduce chamber compliance.191,207–212 In animal studies, propofol does not seem to affect myocardial relaxation or compliance.191 One study in humans using echocardiography has demonstrated that propofol prolongs the IVRT in patients with no history of cardiac disease,199 but does not cause worsening of preexisting diastolic dysfunction.200,213 The impact of etomidate on LV diastolic function has not been studied, but in vitro experiments have shown that it has minimal effects on intracellular calcium metabolism; therefore, it is unlikely that it would affect LV diastolic function.214
SUGGESTED PERIOPERATIVE STRATEGY
The ASE guidelines for assessment of diastolic function recommend a very comprehensive grading algorithm.5 However, the guidelines also recommend a simplified and reproducible approach for individual patients. In the perioperative arena during variable hemodynamics, an approach that rigorously requires the presence of all of the measured variables may be particularly difficult to apply. In one such study, the rigorous application of ASE guidelines for grading diastolic dysfunction during cardiac surgery led to only 20% of the 905 patients being graded as having diastolic dysfunction with no association with postoperative outcome.3 Conversely, when a simplified algorithm (lateral annulus E′ velocity) was used in the same patient group, almost 99% of patients were diagnosed with diastolic dysfunction and demonstrated a significant association with postoperative outcome.3 However, this study is limited by its retrospective nature, the possibility of selection bias, and lack of availability of any hemodynamic data. Validation of such an approach would require prospective application of simplified algorithms, which are modifications of the ASE guidelines.
In anesthetized patients, the ranges of normal values of the Doppler indices of LV filling have not yet been established. Currently, perioperative assessment of diastolic function is based on extrapolation of data obtained during awake-state hemodynamics. According to the ASE guidelines,5 An E′ velocity >8 cm/s essentially excludes the presence of diastolic dysfunction. However, because of the aforementioned factors, TMF and PVF should also be recorded for a comprehensive assessment and interrogation and severity grade assignment (Fig. 4). It is usually not difficult to distinguish an impaired relaxation abnormality (E/A <1, prolonged DT, and S/D >1) from a typical restrictive pattern (E/A >2, short DT, and S/D <1). These findings should be considered in the context of the underlying systolic function and E′ velocity to assign a grade of severity. Systolic function is often within normal limits in most patients with impaired relaxation compared with those with a restrictive pattern. The following caveats should be kept in mind: rhythm other than sinus makes interpretation of E/A and S/D difficult or impossible, “accessory” LV filling with aortic insufficiency, for example, will affect both E/A and S/D, and impaired relaxation will revert to a pseudonormal pattern with increased preload and vice versa. A brief “Valsalva” should be executed; reverse Trendelenburg or a lung recruitment maneuver with a prolonged inspiratory hold will probably unmask preload compensation because increased intrathoracic pressure will decrease blood return to the chest and eventually decrease LA preload. If a normal E/A ratio changes to impaired relaxation, the true underlying diastolic abnormality is most likely a pseudonormal state. A DTI E′/A′ <1 or a Vp <45 cm/s suggests the presence of diastolic impairment; however, the ratio will be decreased once relaxation is impaired.
Regarding estimation of LVFPs, systolic function should be evaluated as the first step. If normal, longer forward flow during atrial systole (A-Ar >0) generally means that the LVFP is normal. The same holds true if the change in E/A ratio with a Valsalva maneuver is <0.5. Retrograde flow for a longer duration during atrial contraction (A-Ar <30 milliseconds) or E/A change >0.5 with Valsalva is associated with increased LVFP. Interestingly, echocardiographic assessment of diastolic function is more reliable if there is concomitant systolic dysfunction because there is less preload effect on E′, Vp and it is easier to apply indices such as E/E′, E/Vp to estimate LVFP. In depressed LVEF, the S/D and E/Vp ratios also provide a clear separation between normal or elevated LVFP, in addition to the aforementioned E/A and A-Ar cutoffs mentioned above. Irrespective of the underlying LVEF, E/E′ <8 and >13 to 15 distinguish normal from elevated LVFP.
The established cutoff values for the various Doppler indices have been derived from TTE studies in awake patients, and may not be entirely applicable to patients examined with TEE under GA. However, in the absence of such normal values, a modified strategy based on the TTE-derived standards should be attempted. Hence, the perioperative approach described in this review, although different, is based on the same principles, avoiding cutoff values of any single Doppler variable. There is no single Doppler index that can diagnose with absolute certainty the presence or absence of diastolic dysfunction. A comprehensive approach should use multiple Doppler modalities with realization of their strengths and weaknesses. Future studies will be needed to establish the standards of LV filling characteristics of patients under GA.
Assessment of systolic function is based on a 2-dimensional examination, whereas diastolic function assessment is performed with Doppler, creating the impression that somehow these 2 exist separately.177 The use of Doppler has allowed us to define events during the cardiac cycle with precision, and to appreciate global myocardial function or performance (combined systolic and diastolic function).154 Newer techniques such as strain, speckle tracking, and velocity vector imaging may allow us to better define the LV filling dynamics and more accurately classify diastolic function. It is now important for anesthesiologists to incorporate Doppler examination of LV filling as part of a “comprehensive” intraoperative echocardiographic examination. In the absence of a specific therapy to improve diastolic function, the impact of routine intraoperative echocardiographic assessment of diastolic function on postoperative outcome is unclear. However, recent evidence suggests that the presence of preoperative asymptomatic LV systolic and diastolic dysfunction is associated with adverse outcome. Anesthesiologists involved in the perioperative care of patients with cardiovascular disorders routinely manage these patients appropriately, perhaps without realizing the stages of diastolic dysfunction. The appreciation of the severity stage of diastolic dysfunction can possibly be used to modify/refine clinical care. For example, during the impaired relaxation phase, augmentation of LA pressure and heart rate control can optimize LV filling by increasing the LA-LV pressure gradient and increasing filling time. However, in the more advanced stage of diastolic dysfunction, fluid restriction and judicious use of diuretics would be the logical therapeutic choices. Future studies will be needed to accurately assess the therapeutic impact of such a strategy.
Name: Robina Matyal, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Robina Matyal approved the final manuscript.
Conflicts of Interest: Robina Matyal reported no conflicts of interest.
Name: Nikolaos J. Skubas, MD.
Contribution: This author helped write the manuscript.
Attestation: Nikolaos J. Skubas approved the final manuscript.
Conflicts of Interest: Nikolaos J. Skubas reported no conflicts of interest.
Name: Stanton K. Shernan, MD.
Contribution: This author helped write the manuscript.
Attestation: Stanton K. Shernan approved the final manuscript.
Conflicts of Interest: Stanton K. Shernan reported a conflict of interest with Philips Healthcare and reported a conflict of interest with E-Echocardiography.
Name: Feroze Mahmood, MD.
Contribution: This author helped design the study, conduct the study, and analyze the data.
Attestation: Feroze Mahmood approved the final manuscript.
Conflicts of Interest: Feroze Mahmood reported no conflicts of interest.
a Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography. Available at: http://www.asecho.org/files/DF.pdf. Accessed May 12, 2011.
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