Evaluation of the Patient with Diastolic Dysfunction

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3 Evaluation of the Patient with Diastolic Dysfunction

Jacob Abraham, Kristian Eskesen, Theodore Abraham

Identifying the Cause of Diastolic Dysfunction

Background

• Abnormal diastolic filling patterns in the presence of normal systolic function should alert the echocardiographer to the possibility of a cardiomyopathy (restrictive, hypertrophic) or constrictive pericarditis.

Restrictive Cardiomyopathy

• Restrictive cardiomyopathies (RCMs) are rare disorders (Table 3-1) that cause abnormal stiffening of cardiac chambers, often associated with increased wall thickness (Figure 3-1). Contractile function is normal except in late stages of disease. Elevation of ventricular filling pressures and inability to augment stroke volume with exercise result in heart failure symptoms. Right heart failure often dominates the clinical picture.

• RCM and constrictive pericarditis (CP) have similar clinical presentations and echocardiographic findings. Differentiating RCM from CP is imperative as CP can be cured with pericardiectomy. The distinction is often difficult to make with echocardiography alone and requires integrating physiologic data from multiple investigations (Tables 3-2 and 3-3).

TABLE 3-1 CLASSIFICATION OF RCMs

Site of Involvement	Classification
Myocardium	Noninfiltrative
	• Idiopathic cardiomyopathy • Familial cardiomyopathy • Hypertrophic cardiomyopathy • Scleroderma • Pseudoxanthoma elasticum • Diabetic cardiomyopathy

Infiltrative

Storage

• Glycogen storage disease

Endomyocardium

• Endomyocardial fibrosis

• Hypereosinophilic syndrome

• Carcinoid heart disease

• Metastatic cancers

• Radiation

• Toxic effect of anthracycline

• Drugs (serotonin, methysergide, ergotamine, mercurial agents, busulfan)

Figure 3-1 2D 4-chamber view showing common findings in RCM, including nondilated hypertrophied left and right ventricles and enlarged left and right atria.

TABLE 3-2 OVERALL ECHOCARDIOGRAPHIC APPROACH FOR ASSESSING DIASTOLIC DYSFUNCTION

Modality	View/Technique	Findings
2D	Apical, parasternal, subcostal	• Nondilated LV • Often increased LV wall thickness • RV free wall thickening • Bi-atrial enlargement • Dilated inferior vena cava
Pulsed wave Doppler	4-chamber: Ultrasound beam aimed at an angle of 20 degrees laterally to apex, and the sample volume between the tips of the mitral valve leaflets	• Varying E, A, E/A, IVRT patterns (see text for details) • Pulmonary hypertension
	Suprasternal short-axis	• Systolic : diastolic ratio of pulmonary forward flow ≤0.4 • Atrial reversal wave ≥35 cm/s
	Subcostal	• Blunted systolic forward flow • Prominant a-wave reversal
Tissue Doppler imaging	4-Chamber: 2-mm sample volume at the medial mitral annulus with the Doppler beam parallel to the longitudinal movement. Gain settings and wall filters should be low and velocity scale expanded.	Varying E, E/E patterns (see text for details)

TABLE 3-3 Approaches and Findings in RCM

Modality	General Findings	Specific Findings
Chest radiograph	Normal-sized heart. Dilated atria. Signs of pulmonary congestion or interstitial edema. Pleural effusion may occur.	Mediastinal lymphadenopathy; pulmonary parenchymal disease in sarcoidosis.
Electrocardiogram	Nonspecific ST- and T-wave abnormalities. Conduction abnormalities. Same chamber and wall dimensions and functions as in echocardiography.	Low voltage in precordial leads is seen in ~50% of patients with amyloidosis with cardiac involvement. Pseudo-infarct pattern (QS wave in consecutive leads) is seen in ~50% of patients with cardiac amyloidosis. Fibrosis caused by cardiac sarcoidosis can be detected with late gadolinium enhancement. Trilaminar appearance (normal myocardium, thickened fibrotic endocardium, and overlying thrombus) may be detectable in endomyocardial diseases. Global reduction in T2* cardiac tissue is commonly seen in hemochromatosis.
CT	Same chamber and wall dimensions and functions as in echocardiography.
Biposy	In most cases nonspecific.	Apple-green birefringence, electron microscopy findings in amyloidosis.
Radionuclide imaging	Mainly nonspecific findings in RCM.	With increased cardiac involvement in amyloidosis, Tc-99m labeled tracers are detectable.
Cardiac catheterization	Nonspecific findings of diastolic dysfunction (increased diastolic pressures, right-sided square root sign, and often LVEDP ≥5 mm Hg greater than RVEDP).

LVEDP, LV end-diastolic pressure; RVEDP, RV end-diastolic pressure; Tc-99m, ^99-mtechnetium.

Echocardiographic Approach

General characteristic findings in RCM include (Figures 3-2 through 3-5):

• Nondilated left ventricle, often with increased wall thickness

• Normal LV systolic function

• Right ventricular free wall thickening

• Marked bi-atrial enlargement

• Dilated inferior vena cava

• Pulmonary hypertension

Figure 3-2 2D 4-chamber view with color Doppler flow showing bilateral atrioventricular regurgitation. Arrowheads mark tricuspid regurgitation (TR) and mark mitral valve regurgitation (MR).

Figure 3-3 Pulsed wave Doppler over mitral valve showing typical signs of restrictive physiology with high (1 m/s) early (E) mitral inflow, increased E/A ratio (2.5), and decreased DT.

Figure 3-4 TDI of medial mitral annulus showing decreased systolic myocardial velocity (S′) and early diastolic myocardial relaxation (E′). A′, myocardial velocity associated with atrial contraction.

Figure 3-5 Severe mitral valve regurgitation due to RCM, indicated by arrows.

Specific Diagnoses

• Cardiac amyloidosis: increased RV/LV wall thickness, thickening of the interatrial septum and atrioventricular valves, presence of a small-to-moderate pericardial effusion, and “speckled” or “granular” myocardium (Figures 3-6 and 3-7).

• Cardiac sarcoidosis: Idiopathic, inflammatory multisystem granulomatous disease that commonly involves the lungs, skin, kidneys, eyes, and heart. Echocardiographic findings include both normal and dilated ventricular chambers; increased wall thickness and wall thinning, depending on stage and treatment, and aneurysm formation; segmental wall motion abnormalities not conforming to a coronary vascular distribution; and akinetic/dyskinetic wall segments adjacent to normokinetic wall segments.

• Glycogen storage disease: Unexplained left ventricular hypertrophy should prompt consideration of hypertrophic cardiomyopathy (HCM; see below) and the following glycogen storage disorders:

• Fabry’s disease: X-linked autosomal recessive disorder caused by lack of α-galactosidase A, leading to intracellular accumulation of ceramide trihexoside. The echocardiographic appearance is similar to HCM (see below). A specific finding for Fabry’s disease is a binary appearance of the LV endocardial border, reflecting the endocardial and subendocardial compartmentalization of glycosphingolipid material.

• Danon’s disease: X-linked disorder typically affecting young men (<20 years old) caused by deficient lysosomal-associated membrane protein 2 (LAMP2). Phenotype of marked concentric HCM (wall thickness 20 to 60 mm) with severe LV systolic dysfunction, often associated with ventricular preexcitation. Extracardiac clinical features include skeletal myopathy, mental retardation, and hepatic disease, but systemic features may be absent or minimal.

• PRKAG2 cardiomyopathy: Autosomal dominant mutation in regulatory subunit of AMP-activated receptor kinase. Electrocardiographic (ECG) findings include preexcitation. Differentiated from Danon’s disease clinically by absence of systemic disease.

Figure 3-6 Four-chamber view of patient with amyloid. Enlarged walls and sparkling granular appearance are characteristic. IVS, interventricular septum.

Figure 3-7 M-mode through right and left ventricles helps quantifying discrete pericardial effusion (PE), a typical finding in RCM.

Physiologic Data

• M-mode through the interventricular septum and inferior wall can reveal a square root sign.

• Diastolic mitral regurgitation (MR) may be present if left ventricular diastolic pressure is markedly elevated.

Anatomic Imaging (Acquisition/Analysis/Pitfalls)

• Abnormal diastolic filling patterns ranging from E/A reversal (grade I) to a restrictive filling pattern (grade IV) can be seen depending on the stage of disease and volume status.

• The term “restrictive pattern” is used to describe a high mitral E velocity seen in conditions of elevated atrial pressure and abbreviated early diastolic filling time (short DT). This pattern is not synonymous with RCM and can be observed in any cardiomyopathy leading to elevated ventricular filling pressures.

• Tissue Doppler imaging (TDI) myocardial velocity is recorded from the apical 4-chamber view. A small sample volume (2 mm) is positioned at the medial mitral annulus. The image should be optimized so that longitudinal deformation is parallel to the Doppler beam.

• Gain settings and wall filters should be low (i.e., <100 Hz) with an expanded velocity scale. A low early diastolic relaxation (E) (<8 cm/s) suggests RCM, whereas a high E (>12 cm/s) suggests CP. Caution is needed in interpreting Em in patients who may have confounding conditions (e.g., myocardial infarction, mitral annular calcification, right ventricular pressure overload) that can also impact septal TDI velocity.

Alternative Approaches

See Table 3-3.

Endomyocardial Fibrosis

• Endomyocardial fibrosis is a very rare form of RCM occurring in the hypereosinophilic syndrome, seen in Latin America, Africa, and Asia.

Key Points

• The apex of the right or left ventricle is obliterated by thrombus, then fibrosis, in the absence of an underlying wall motion abnormality.

• Thrombus formation beneath the posterior papillary muscle and thickening of mitral valve leaflets with restricted motion can result in significant MR.

• Basal hypercontractility (“Merlon sign”) is present.

Hypertrophic Cardioymopathy

• Autosomal dominant genetic myocardial disease with variable penetrance caused by mutations in genes encoding sarcomeric proteins and other genes.

Key Points

• Patterns of left ventricular hypertrophy

• Type 1: hypertrophy limited to anterior septum (Figures 3-8 and 3-9)

• Type 2: hypertrophy involving the entire septum

• Type 3: diffuse hypertrophy sparing the basal posterior wall

• Type 4: apical hypertrophy (Figure 3-10)

• Echo contrast may be needed to define the endocardial border and demonstrate apical hypertrophy. Color or pulsed wave Doppler examination may also show absent blood flow. The ECG in apical hypertrophy often displays characteristic deep precordial T-wave inversions.

• The thickness of the basal posterior wall is usually normal.

Figure 3-8 Short-axis view of LV in a patient with anterior HCM. Upper white arrows indicate severe thickening of anterior septal LV wall. Lower white and black arrows indicate less hypertrophy in posterior LV wall.

Figure 3-9 Patient with HCM mainly affecting the basal part of the septum. Arrow indicates a septal “knuckle.”

Figure 3-10 Two-chamber view of LV showing nondilated apical hypertrophy in patient with HCM. Arrowheads indicate apical hypertrophy.

Dynamic LV Outflow Tract (LVOT) Obstruction

• Narrowing of the outflow tract from hypertrophy

• Systolic anterior motion (SAM) of the mitral valve and submitral structures

• Hydrodynamic drag forces (Venturi effect)

• Midsystolic closure of the aortic valve due to early LV emptying

• Correlation between the extent and pattern of hypertrophy and the degree of obstruction

• Resting obstruction common in patients with extensive septal hypertrophy

• Late-peaking, high-velocity flow in the outflow tract with typical “dagger” shape (Figure 3-11)

• Worsening of outflow obstruction with post–premature ventricular contraction beat, amyl nitrate, or Valsalva maneuver (Figure 3-12)

Figure 3-11 Pulsed wave Doppler through LVOT shows signs of obstruction revealing the characteristic “dagger”-shaped flow.

Figure 3-12 Pulsed wave Doppler of patient with HCM, showing difference in gradient with and without Valsalva maneuver.

Mitral Regurgitation

• SAM of the mitral valve and submitral structures contributes to LVOT obstruction.

• Anterior displacement of the anterior mitral leaflet in systole causes posterior MR in mid- to late systole. Non-posterior MR suggests intrinsic mitral valve disease.

• Repeated contact between the mitral valve and septum can cause thickening of the anterior mitral leaflet and subaortic septal endocardial fibrosis.

Overview of Echocardiographic Approach

Acquisition

Alternative Approaches

• Cardiac magnetic resonance imaging (MRI) has emerged as a useful tool for diagnosing HCM by the magnitude and distribution of hypertrophy ⁷ and in prognosis (extent of delayed gadolinium enhancement, a radiographic surrogate for myocardial fibrosis, may predict sudden cardiac death).⁸

RCM versus Constrictive Pericarditis

• Because the rigid pericardium does not effectively transmit respiratory changes in intrathoracic pressure to the heart, the transmitral filling gradient decreases with inspiration and increases with expiration. Reciprocal respiratory changes occur in the right ventricular filling gradient. Consequently, ventricular interdependence is present and even enhanced in CP, but absent in RCM because of involvement of the ventricular septum. This provides the basis for the specific differences in M-mode, 2D, and Doppler findings between RCM and CP (Table 3-4).

• Diastolic dysfunction in CP is due to epicardial tethering and pericardial constraint, resulting in reduced circumferential deformation. In contrast, RCM is due to subendocardial dysfunction, resulting in reduced longitudinal deformation. Speckle tracking imaging to assess strain can aid in differentiation of RCM and CP (see Table 3-4).

• Respiratory variation (>30%) in transmitral and trans-tricuspid inflow suggests CP. A respirometer is used to clearly identify inspiration and expiration. 2D and color flow images are used prior to Doppler measurement to ensure minimal respiratory variation in the angle between the ultrasound and direction of blood flow.

• Pulmonary artery pressure is typically normal in CP and elevated (secondary to elevated LV pressure) in RCM.

TABLE 3-4 RESTRICTIVE CARDIOMYOPATHIES Versus CONSTRICTIVE PERICARDITIS

Approach

• Early diastolic filling is rapid with CP and reduced with RCM early in the disease course.

• Caveats

• Respiratory changes in transmitral inflow may be absent in up to 20% of patients with CP because of a concurrent restrictive process or because of markedly elevated atrial pressures. In the latter circumstance, respiratory changes in left atrial pressure have relatively little effect on filling when the driving pressure (left atrial pressure − left ventricular pressure) is high. Reducing preload (by placing the patient in a sitting position or by Valsalva maneuver) may unmask respiratory variation in E-wave velocity.

• Respiratory variation in diastolic filling is not specific for CP and may be seen in other conditions associated with exaggerated swings in intrathoracic pressure, such as asthma or chronic obstructive pulmonary disease. Measurement of flow velocity in the superior vena cava in pulmonary disease will show a marked increase in flow during inspiration because of the large negative intrathoracic pressure generated. No such changes are seen in CP or RCM.

Monitoring Effects of Treatment

Lusitropy

• The effect of interventions on diastolic function has recently become an endpoint in clinical trials. Tissue Doppler echocardiography has improved assessment of diastolic function by enabling distinction between normal and pseudonormal transmitral Doppler filling patterns.

Control of Blood Pressure (BP)

Mass

• BP potently influences LV mass. Antihypertensive drug classes have heterogeneous effects on LV mass for equivalent degrees of BP reduction.

• 2D targeted M-mode

• In the parasternal short-axis view, a circular cross section at the level of the mitral leaflet tips is chosen. Eccentric cross sections should be excluded.

• Choose beats with optimal definition of the posterior wall epicardial-pericardial interface.

• Average beats from passive end-expiration during quiet respiration.

• Measure left ventricular diastolic internal dimension (LVIDd), and septal thickness (STd), and posterior wall thickness (PWTd).

• Mass = 0.8[1.04 (STd + LVIDd + PWTd)³ − (LVIDd)³] where 1.04 gm/mL is the specific gravity of myocardium and 0.8 is a correction factor (cube formula).

• Assumes prolate ellipsoid geometry; thus it is invalid if regional wall motion abnormality or distorted chamber geometry is present.

• 2D echocardiography ⁹

• Cylindrical hemi-ellipsoid area-length method