1. Assessment of Left Ventricular Systolic Function
Riya S. Chacko, MD
March 4, 2009

2. Clinical Significance
Clinical decisions based on systolic function -> MADIT II, SCDHeFT trials for ICD implantation for those with depressed EF with or without coronary disease
Heart failure management including cardiac resynchronization therapy
Coronary disease -> prognosis, evaluation
Use of cardiotoxic medications such as some chemotherapeutic agents
SCDHeFT did not mandate imaging modality (echo 58, RNA 24%, and RVG 17% with no stat sign difference in survival despite sign. Differences in EF)
Herceptin (Trastuzumab) should not be commenced in patients with EF <55%. Nor should it be continued in those with >10% drop in EF or to <50%

3. Definition of Ejection Fraction
(EDV – ESV)/EDV
Or stroke volume/EDV

4. Clinical Relevance of EF Variability
Mean EF as measured by RNA was 25.1% ± 6.9%; by
echocardiography, 23.8 ± 6.9%; and by angiography, 21.9 ± 6.9%. These measures were significantly different (P b .001),
and each pairwise comparison differed significantly (P b .001 for each). Multivariable analysis showed no significant
difference in survival between patients enrolled based on RNA versus echocardiography (HR 1.06, 95% CI ), RNA
versus angiography (HR 1.25, 95% CI ), or echocardiography versus angiography (HR 1.18, 95% CI ).
Gula L. et al. Am Heart J 2008;156:

5. Correlation vs. Agreement
Correlation coefficient describes the linear relationship between 2 variables. Closer to 1 or -1 means stronger correlation.
Difference between correlation coefficient and agreement. Correlation coefficient (CC) may be high with poor or moderate agreement (ie, EF differs by 20%)
One study shows high correlation between 2D echo, RVG, and contrast left ventriculography but only moderate agreement (1)

6. Correlation
The broader the range of values studied (ie EF) the higher the r value or correlation even though agreement may not differ (McGowan)
Bland JM, Altman DG. (1986). Statistical methods for assessing agreement between two methods of clinical measurement. Lancet, i,

7. Agreement
Bland JM, Altman DG. (1986). Statistical methods for assessing agreement between two methods of clinical measurement. Lancet, i,

8. (1) Naik MM. J Am Coil Cardiol 1995;25:937-42)
Note Starling had intermediate correlation at 0.81 but broad range of agreement from 26 to 20.8 and Folland although had narrower agreement had lower correlation coefficient
(1) Naik MM. J Am Coil Cardiol 1995;25:937-42)

9. Imaging Modalities Used to Assess LV Systolic Function
2D Echocardiography
Contrast echocardiography
3D Echocardiography
Radionuclide ventriculography (MUGA, ERNA, RNA)
MRI
Gated SPECT CT
Contrast cineventriculography (ventriculogram on catheterization)
Myocardial Strain, Simpson’s Rule, Displacement

10. 2 Dimensional Echo
Depends on identification of endocardial border and image quality
Many methods of assessing LV systolic function both qualitative and quantitative
Visual estimation using the 17 segment model or wall motion index (WMI)
Quantitative assessment using M-mode, strain, displacement, speckle tracking, Simpson’s Rule, use of contrast agents
WMI scores each segment : 1 normal motion or hyperkinesia, 2 hypokinesia,
3 akinesis, 4 dyskinesia, 5 aneurysmal.
Regional wall motion is scored in all standard 2 views. 9-segment model, LVEF = 30WMI
Visual assessment and WMI may be as good if not better (McGowan) at assessing EF in those with RWMA or poor echo pictures but less accurate in afib.

11. Simpson’s Rule http://depts.washington.edu/cvrtc/simplvgm.html
Known as the “disc summation method” allows volume estimates based on 2D pictures. Trace the endocardial border in 2 orthogonal planes (apical 4 and 2 chamber) or 1 view. It is the recommended echo way to assess EF.
Assumes symmetric geometry and studies that proved its accuracy were mostly performed in people with preserved EFs (>40%).
Interestingly, in post-MI studies, visual estimation of EF (based on regional WMA) had better correlation and agreement than Simpson’s Rule. Therefore, less useful in poor EF, RWMA (post-MI) or dilated CM.

12. Concepts of LV Strain
Defined as (L-Lo)/Lo where L is the length at the end of systole and Lo is the original length
Measure tissue deformation
May be obtained through M-mode, tissue doppler or speckle tracking
As muscle contracts, it shortens in the longitudinal and circumferential axis (negative strain) and lengthens in the radial axis (positive strain). Taken from apex, negative during systole and positive during diastole.
Associated with loading conditions. Increased pre-load increases strain, increased afterload decreases strain
Strain rate, more a measure of contractility than regional EF (strain), is less dependent on loading conditions.

13. Ping Sun J et al. (J Am Soc Echocardiogr 2004;17:132-8.)
Regression calculation gives strain rate curve
Integrate C to get D (strain)
Ping Sun J et al. (J Am Soc Echocardiogr 2004;17:132-8.)

14. LV Strain Rate Defined as Va-Vb/L Velocity at point (a)
Velocity at point (b)
L is the distance between both points

15. Normal Values of Systolic Myocardial Strain
Normal longitudinal systolic strain in most segments varies from 15% to 25%, with normal radial strains ranging from
50% to 70%, and standard deviations of 5% to 7% (22). Normal resting values for longitudinal
SR vary between 1.0/s and 1.4/s, with the standard
deviation in most locations ranging from 0.5/s to 0.6/s.
Ping Sun J et al. (J Am Soc Echocardiogr 2004;17:132-8.)

16. Limitations of LV Strain
Limited by noise measurements
Angle of the doppler must be parallel to the myocardium and thus, useful only in the long axis
Angles changes during cardiac cycle and respiration

17. Speckle Tracking Based on B-mode harmonics
Tracks characteristic speckle patterns based on interference from ultrasound waves and myocardium
Angle-independent

19. Speckle vs. MRI Amundsen BH et al. (J Am Coll Cardiol 2006;47:789 –93)
Amundsen et al showed in a study of 9 mongrel dogs, that speckle and MRI tagging had good correlation
Amundsen BH et al. (J Am Coll Cardiol 2006;47:789 –93)

20. Advantages of 2D Echo No radiation exposure Portable
Accurate assessment of regional wall motion abnormalities
Image acquisition not limited by presence of arrhythmias
Assessment of other cardiac structures (ie valves, etc)
Although not limited by arrhythmias, EF is influenced by, for example, presence of afib. Among studies of subjective visual
assessment, 95% CIs were 19% to 24% versus
16% to 18% in groups with and without
atrial fibrillation subjects, respectively.
Methodological differences. (McGowan)

21. 2D Echo Limitations Poor test-retest reliability Geometric assumptions
Dependence on variable loading conditions
Image quality – operator dependent and poor endocardial borders in 5-10% (12)
Although effective for single assessment, less producible with serial assessments
Dependent on image quality, loading conditions, off-axis cuts, and geometric
Example of systolic function dependent on loading conditions: inaccurately high EF with mitral regurgitation or low EF with severe aortic stenosis
Improvements include harmonic imaging and contrast (enocardial border)

22. Comparing RVG to Echo Echocardiography detected 14 out of 15 patients
with LVEF <40%, as estimated by radionuclide ventriculography (sensitivity=93%), and 32 out of 34 patients with LVEF >40%, as estimated by radionuclide ventriculography (specificity=94%). The overall accuracy of echocardiography in identifying patients with a low ejection fraction was 94%.
But test-retest correlation much lower for 2D echo than other modalities such as 3D echo (22)
R Senior et al. European Heart Journal (1994) 15,

23. Contrast Echocardiography
Utilizing microbubbles or fluorcarbon gas to stabilize bubbles such as Optison or Sonovue
Major clinical use at this time is to assess LV function by enhancing endocardial borders
Especially in those with less than 80% of endocardial border identified or those in ICU setting (mechanical ventilation)
It is believed that 37% more diagnostic information may be obtained with contrast and even up to 50-90% improvement if poor echo windows in non-contrast studies (4)
Michael Stewart. Contrast echocardiography.

24. A = end diastole, B = end=systole in a patient with a recent MI where lateral wall not visualized. C and D with contrast showing lateral wall thickening.
Hoffman et al found that the mean difference btwn echo and MRI differed by less than 5% and that correlation increased from 0.60 to 0.77 with addition of contrast

25. Assessment of Regional Wall Motion
8 European Centers enrolled 100 patients to each have CVG, contrast echo and MRI within 72 hours of each other for LV assessment.
Interobserver agreement expressed as kappa coefficient was 0.41 (range 0.37 to 0.44) for unenhanced echocardiography, 0.43 (range 0.29 to 0.79) for cMRT, 0.56 (range 0.44 to 0.70) for cineventriculography, and 0.77 (range 0.71 to 0.88) for contrast echocardiography.
Accuracy to detect EPD-defined RWMA was highest for contrast echocardiography, followed by cMRI, unenhanced echocardiography, and cineventriculography.
Hoffmann R et al. (J Am Coll Cardiol 2006;47:121– 8)

26. Hoffmann R et al. (J Am Coll Cardiol 2006;47:121– 8)
Comparison of all 4 modalities showed an inferior/inferolateral WMA that was not detected on 2D echo without contrast due to poor visualization.
In this study, contrast echo showed an improved agreement with MRI as compared to NCE. Hoffman also demonstrated an increase in interobserver agreement with CE vs. NCE. MORE DETAILS OF TRIAL !!!
Hoffmann R et al. (J Am Coll Cardiol 2006;47:121– 8)

27. Hundley et al. J Am Coll Cardiol 1998;32:1426 –32.
In this study by Hundley et al from UTSW and UNC, a total of 35 patients underwent both MRI and echocardiography and they found correlation coefficients of >0.92.
However, with the addition of contrast, the limits of agreement narrowed. Moreover, they found that CE was most helpful in increasing the accuracy for LVEF quanitification in patients with intermediate EFs btwn 25 and 50%.
Hundley et al. J Am Coll Cardiol 1998;32:1426 –32.

28. Table from Dr. Vinay Bhatia in his review of contrast echocardiography demonstrating trials that have shown consistent increased agreement between CE and MRI (often gold standard)
Bhatia et al Journal of the American Society of Echocardiography May .

29. 3D Echocardiography
Attempts to use 3D echo rely on less geometric assumptions as compared to 3D echo
3D analysis minimizes variation in EF assessment

30. Limitations of 3D Echo Large hearts (increased LV volume)
Image quality - Inability to differentiate endocardial borders

31. Intra and Inter-observer variability
In this study, 50 patients underwent 2D and 3D echo + MRI. Retest variation was observed within 1 hour by complete repeat of exam by a different ultrasonographer. LV volume was statistically underestimated by 2D (less so by 3D) but ejection fraction by all 3 methods was similar.
Jenkins et al.

32. 3D versus 2D as compared to MRI
Both 2D and 3D underestimate LV mass but 3D less so.
Jenkins et al.

33. CMR versus 3D Echo Soliman O et al. Am J Cardiol 2008;102:778 –783
Linear regression from a sample of 24 patients (both ischemic, idiopathic and healthy) showing correlation by CMR and 3D echo for LVEF.
Inter-observer variability was 7.6% for LV ejection fraction, and intra-observer variability was 6.0%.
Soliman O et al. Am J Cardiol 2008;102:778 –783

34. Contrast 3D Echocardiography
39 patients with 3D echo with and without contrast as well as MRI within the same day, After contrast agent
enhancement, mean image quality index improved from to (p <0.001).
Contrast agent–enhanced RT3DE measurements showed better correlation with MRI (LV
end-diastolic volume, r vs 0.86; LV end-systolic volume, r vs 0.94; LV ejection
fraction, r vs 0.81). The limits of agreement (Bland-Altman analysis) showed a
similar bias for RT3DE images with and without contrast agent but with smaller limits of
agreement for contrast agent–enhanced RT3DE. Also, inter- and intraobserver variabilities
decreased. In a subgroup, patients with poor to moderate image quality showed an
improvement in agreement after administration of contrast agent (24.4% to 12.7%) to
the same level as patients with moderate to good image quality without contrast agent
(10.4%).
Krenning et al.

35. Radionuclide Angiography
Introduced in the 1970s as a “gold standard” against invasive ventriculography for accurate assessment of LV function
Technetium-labeled erythrocytes or albumin
“Pre-tinned” with a stannous agent (Sn+2) which crosses easily across the RBC membrane and binds to cellular components. Serves as chelating agent for technetium- 99m pertechninate (binds to hemoglobin)
Certain drugs interfere with RBC labeling such as: doxorubicin and epirubicine. No interactions with human serum albumin (HSA).

36. RVG Two types: first pass and equilibrium gated RNA or MUGA
Radionuclide ventriculography is used for assessment of dilated cardiomyopathies in presence of cardiotoxic drugs (chemotherapy)
Right ventricular dysplasia
Aortic regurgitation
Cardiac resynchronization therapy
Lung transplantation candidates : RV assessment
Technetium 99m-pertechnenate is then injected 30 min. later, diffuses across RBC and binds to Hgb. Stannous agent serves as chelator. If pertechnenate is reduced out RBC, cannot diffuse across and instead has high background activity.
RBC labelling may be affected by certain drugs
B. Hesse et al. EANM/ESC guidelines for radionuclide imaging of cardiac function. Eur J Nucl Med Mol Imaging (2008) 35:851–885

37. RVG
Normal values are center-dependent (ie, could range from 35-75% as normal)
EF assessed by creating ROI (region of interest) around LV at end-diastole and then background ROI at end-systole.
A time activity estimated stroke volume using EDV and ESV is used to calculate EF.
Highly reproducible quantification of EF
EF can also be assessed during exercise
No assumptions made about geometry
Usually bike exercises

39. RVG
Folland EG et al. JNuclMed 18: , 1977

40. First Pass RVG Technique

41. Limitations of RVG Radiation dose 4.9-5.6 mSv.
Relative contraindication in pregnancy and lactating women.
In MUGA, there is an overlap of cardiac chambers (vs. first pass)

42. Folland.

43. Best correlation of EF by CVG and RNA is EF less than 55%
Best correlation of EF by CVG and RNA is EF less than 55%. Correlation coefficient of 0.86 and Folland reported CC of serial exams was 0.92
Folland et al.

44. Bellenger et al. compared RVG vs
Bellenger et al. compared RVG vs. 2D echo (Simpson and M-mode) and cardiac MRI to assess LVEF and found a statistical difference between all except Simpson 2D and MRI.
Naik et al reported variation of echo EF of 40% with EF of 20-60% by RNA despite an excellent correlation coefficient of (1)
In Naik’s study, echo had an intra-observer variability of 4.4% and inter-observer variability of 6.1%. RNA had 2.5% and 6.8%.
In Naik’s study, echo had an intra-observer variability of 4.4% and inter-observer variability of 6.1%. RNA had 2.5% and 6.8%.

45. Cardiac MRI Assesses volume by a disk summation method.
This may inaccurately include basal structures such as the aortic root or left atrium at the level of the mitral valve.
Considered the “gold standard” for EF measurement
Shows a high level of reproducibility
Advantages include: lack of radiation exposure,
avoidance of contrast media injection, and excellent temporal and acceptable spatial resolution
Ways to overcome inaccuracies of MRI and volume are increasing the number of disks and thus decreasing the thickness of each one.

46. Limitations of Cardiac MRI
Expense
Availability
Limited use in cardiac patients with defibrillators/pacemakers and heart failure

47. Cardiac CT
In a study by Dewey et al, 88 patients underwent MSCT, CVG and MRI. Echo was retrospectively analyzed in a subset.
Agreement was significantly superior for MSCT than for
CVG ( 10.2% vs %; p ) and Echo ( 11.0% vs %; p ).
For the end-diastolic and end-systolic volumes, the limits of agreement with CVG (p ) and Echo (p and p 0.02, respectively) were also significantly larger than with MSCT.
Radiation varies from 1-2 mSv2
Sievert

48. Intra-observer analysis of MSCT yielded limits of agreement for ejection fraction ( 4.8%), end-diastolic volume ( 15.6 ml) and end-systolic volume ( 8.0 ml), and myocardial mass ( 18.2 g).
The accuracy in identifying patients and myocardial segments with abnormal regional function was significantly higher with MSCT (84% and 95%) than with CVG (63% and 90%; p and p ), whereas MSCT and Echo were not significantly different in identifying patients with abnormal regional function.

49. In a study of 88 patients, MSCT, CVG and echo within 48 hours.
Dewey et al.

50. Short axis views when endocardial and epicardial borders are identified and used to identify thickness, ESV and EDV,
MDCT may underestimate EF 1-7% compared to CMR (Juergens).
The inter-observer variability was from 2% to
11% for LV-EDV and from 6% to 9% for LV-ESV (Fig. 12);
corresponding values for CMR are 2–6%

51. Intraobserver Variability
On second analysis, 90% of patients were assigned to the same category with statistically “good agreement”.
For the 29 randomly selected
patients who had intraobserver variability of MSCT analyzed
after an interval of at least 6 months, the limits of
agreement for ejection fraction, end-diastolic volume, endsystolic
volume, and myocardial mass were 4.8%, 15.6
ml, 8.0 ml, and g, respectively, demonstrating a
low variability for MSCT.
As compared to MRI, the sensitivity to detect regional wall motion dysfunction was 75% for MSCT versus 38% for Vgram
Accuracy of MSCT was 94.9% and specificity was 96.8%
Dewey et al also found that while echo and MSCT had no statistical differences in detecting regional abnormalities, there was a stat difference in the agreement of LVEF and was superior in MSCT.
Noncontrast echo versus MRI shows limits of agreement of 21% and with contrast, reduced to 17%. Dewey et al showed agreement of 10% with MSCT.
Dewey et al.

52. Limitations of Cardiac CT
Poor temporal resolution and radiation exposure have limited use of MDCT to assess LV function
Decremental decrease in image quality in systole

53. Brodofoel used a dual-source CT to improve temporal resolution in 20 patients
A and B are from dual source CT and C and D from MRI. Measurements shown in end diastole and end systole.

54. Statistical Correlation of EF by MRI and CT
Very good agreement of 96.7% myocardial segments for regional wall motion abnormalities.
Brodofoel et al.

55. Agreement between Regional Wall Motion Dysfunction
A study from MGH showed Bland-Altman analysis
revealed a trend of multidetector CT
slightly underestimating LV EF compared
with TTE (mean difference, 2% 12)
(Fig 2). The interobserver reliability for
assessment of global LV EF with multidetector
CT was excellent (r 0.83).
The interobserver reliability for assessment
of global LV EF with echocardiography
was good (r 0.68) (Fig 3). Bland-Altman analysis
was good (r 0.68) (Fig 3). Cury et al. Although the temporal resolution of
multidetector CT (82–165 msec) is still
inferior to that of TTE, we found that
abnormal systolic function in terms of
RWM could be discerned in almost all
cases of MI. Further, multidetector CT
was not limited by poor acoustic echocardiographic
windows. It is also important
to point out that the detection of
acute MI in patients by using multidetector
CT was not inferior to that of TTE
(similar accuracy of 96%) and that the
interobserver reliability for EF quantification
was better with multidetector CT
(r 0.83), as compared with TTE (r
0.68).
Brodofoel et al.

56. Gated SPECT
Utilizes either thallium or technetium 99m tracers such as tetrofosmin or sestamibi.
Utilizes the concept of partial volume effect or recovery coefficient which means the brightness of the tracer varies with the thickness of the wall (despite same level of tracer). Thus, in systole, walls are brighter.
Automated evaluation of EF using endo and epicardial borders to create a 3D display

58. Correlation between Thallium and MIBI
Germano G et al.

59. SPECT vs. Echo Nichols et al compared SPECT to 2D echo
By ANOVA, there were no significant differences among ejection fractions (EFs), but there were for volumes.
Linear regression analysis comparing gated SPECT and echocardiographic volumes showed a nearly identical strong correlation (r = 0.92; P < )
J Nucl Med 2000; 41:

60. Analyzed 3 computer models from SPECT to assess EF versus echo.
Reproducibility of SPECT image inversion
ejection fractions was excellent (intraobserver r = 0.99, interobserver
r = 0.93). Williams et al.

61. Gated SPECT Disadvantages
Limited by arrhythmias by ECG-gating (22)
Attenuation, fixed perfusion defects may incorrectly underestimate wall thickening and thus underestimate LVEF
Radiation exposure equals that of an RVG

62. CVG
Biplane 30 degrees RAO and 60 degrees LAO or single view

63. Left ventricle assumed to be an ellipsoid
15 to 60 frames per second (fps), and radiographic contrast material is usually injected into the left ventricle at rates of 7 to 15 mL/ sec for a total volume of 30 to 50 mL
Left ventricle assumed to be an ellipsoid
Grossman and colleagues in 1978 proved that the volume calculcated by CVG correlated well with post-mortem casts made of the LV.
Fifer MA and Grossman W.

64. Initial comparisons to MRI
Stratemeier et al compared 22 patients undergoing Vgram and cine MRI within 3 days. See correlation between EFs.
Stratetmeier et al.

65. Confirmed by Utz et al.
Difference between EF by MRI and CVG by Hoffman et al was 5.8%. Hoffman R et al found a large inter-observer variability with CVG bringing into question role of EF assessment (European Heart Journal (2005) 26, 607–616)
Difference between EF by MRI and CVG by Hoffman et al was 5.8%. MRI and CVG had only moderate agreement. CVG overestimated EDV and ESV.

66. Limitations of CVG Radiation exposure Invasive risk of procedure
Geometric assumptions on biplane view
Contrast medium risk

67. In Summary… Many different imaging modalities used to assess EF.
However, EF interpretation is not interchangeable among the studies despite good correlation.
Choice of modality should reflect understanding of intra and inter-observer variability.
Exposure to radiation also a consideration.

68. Imaging Modalities Used to Assess LV Systolic Function
2D Echocardiography
Contrast echocardiography
3D Echocardiography
Radionuclide ventriculography (MUGA, ERNA, RNA)
MRI
Gated SPECT CT
Contrast cineventriculography (ventriculogram on catheterization)
Myocardial Strain, Simpson’s Rule, Displacement

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