Intraventricular dyssynchrony in light chain amyloidosis: a new mechanism of systolic dysfunction assessed by 3-dimensional echocardiography

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Abstract

BACKGROUND
Light chain amyloidosis (AL) is a rare multiorgan disease with extracellular deposition of fibrillar amyloid proteins derived from immunoglobulin light chains 1, 2. Amyloid deposits in the heart, kidneys, liver and nervous system cause organ failure. There is poor prognosis with median survival of 4 months with heart failure 3, 4. It is associated with diastolic dysfunction but often preserved left ventricular (LV) ejection fraction, especially in the early stages 5-9. Left ventricular dyssynchrony is common in heart failure patients and may contribute to its pathophysiology10. Intraventricular dyssynchrony reduces ventricular efficiency and cardiac performance 11 while cardiac resynchronization therapy improves symptoms and prolongs life 12, 13. Amyloid deposition can potentially alter regional cardiac mechanics. In a recent paper, Bellavia, et al. reported that patients with less advanced AL cardiac amyloidosis had increased segmental dyssynchrony compared to controls, but more advanced amyloidosis was associated with hypersynchronization using Doppler tissue velocity imaging 14. Three dimensional (3D) assessment of regional dyssynchrony has potential advantage over 2-dimensional based tissue Doppler studies as the temporal relationships of all 16 segments can be related with ease. Recently, 3D echocardiography has been utilized to study the temporal pattern of the dispersion in segmental ventricular volumes during the cardiac cycle in the novel assessment of ventricular dyssynchrony 11, 15. The dispersion (expressed as standard deviation) of the duration/timing from beginning of systole to the minimal systolic volume in the 16 different regions of the left ventricle (16-SD%, normalized to cycle length) has been shown to be a marker of dyssynchrony that was associated with ventricular dysfunction 11, 15. We hypothesize that AL subjects have left ventricular dyssynchrony compared to healthy controls. The aim of the study was to compare 16-SD% in AL subjects versus healthy controls.

METHODS

Patient Population

Ten consecutive biopsy-proven AL subjects undergoing workup at 1 institution and 10 healthy controls underwent 3D echocardiography (60±3 versus 52±1 years, p=NS; 5 females in each group). The diagnosis was initially confirmed by biopsy for light chain amyloid in kidneys (n=4), cardiac (n=3), bone marrow (n=2), gastrointestinal tract (1), fat pad, axillary mass (n=1 each). Among AL subjects, 7 had cardiac involvement as defined by cardiac biopsy or subendocardial late gadolinium enhancement on routine magnetic resonance imaging 16, 17. Three AL subjects without cardiac biopsy or late gadolinium enhancement on MRI had thickened anteroseptum or increased left ventricular mass index on echocardiography.

The study was approved by the local Institutional Review Boards (IRB) and is in compliance with the Helsinki Declaration. All healthy controls gave informed consent. 9 AL subjects signed informed consent as part of a prospective observational study of biopsy-proven AL subjects. 1 AL subject who had tissue biopsy confirmation of the disease at post-mortem did not provide informed consent and waiver of consent authorization was obtained from the IRB.

3D Echocardiography Imaging and Analysis
In all subjects, cardiac 3D full-volume datasets were acquired from the apical window using either an IE33 or Sonos 7500 echocardiograph and X3-1 and X4-2 full matrix-array transducer (Philips Medical Systems, Bothell WA). The full volume data sets consisted of 4 real-time subvolumes acquired during 4 cardiac cycles that are subsequently combined to create a full 3D pyramidal data set. The data sets all had evaluable endocardial borders.

The 3D volume dataset were analyzed by software (QLAB version 4.2, 3DQ Avanced, Philips Medical Systems, Bothell WA) similar to previously published procedure 11. In brief, 2-dimensional orthogonal planes representing the standard apical 4-chamber, apical 2-chamber and LV short axis were oriented to bisect the LV and incorporate the true LV apex. Five anatomic landmarks were set that included septal, lateral, anterior, inferior mitral annulus and the apical endocardium in both beginning and end of systole. The software then recreated a 3D model of the endocardial border at beginning and end of systole using automated border detection algorithm. Manual correction of endocardial border was done if necessary. The software then performed volumetric analysis creating a cast of the LV cavity throughout the cardiac cycle.

The LV was divided into 16 segments (excluding the apex) as per American Society of Echocardiography recommendations 18. The volume of each segment was plotted as a function of time throughout the cardiac cycle, with time normalized to the cycle length and expressed as % R-R interval to account for differences in heart rate. The time from end of diastole (beginning of systole) and minimal systolic volume was quantified for each segment and the standard deviation of these times for the 16 segments (16-SD%) was calculated. The 16-SD% has been previously shown to be a reliable measure of dyssynchrony 11, 15, 19.

Two investigators (RQM and LH) trained in 3D volume analyses independently measured the 3D dataset blinded to disease condition and measured the subjects in random order. The first investigator repeated the measurement greater than a week after the first measurement in random order and still blinded to subject condition . Left ventricular mass index (LVMI) was calculated by Devereux™s formula using the diastolic left ventricular internal diameter, anteroseptal thickness and inferolateral thickness 20. Left atrial volume index was calculated using area-length method as per American Society of Echocardiography standards 21. In AL subjects, the lateral mitral annular velocity (E™), mitral inflow velocity (E) and ratio (E/E™) were obtained using standard pulsed spectral Doppler echocardiography 22.

Data Analyses and Statistics
Data are expressed as mean ├é┬▒standard deviation. Continuous variables were compared by unpaired Student™s t- test for normally distributed data or Mann-Whitney rank-sum test for non-normally distributed data. Correlation analysis was performed using Pearson™s correlation. Intraobserver and interobserver agreement was assessed using intraclass correlation coefficient (ICC) analyses and method of differences by Bland-Altman. For the ICC, a two-way mixed model absolute agreement type was used 23. In this analysis, ICC values less than 0.4 indicate poor reproducibility, values between 0.4 to 0.75 indicate good reproducibility and greater than 0.75 shows excellent reproducibility 23, 24. Limits of agreement were assessed by plotting the differences in the measurement of 16-SD% against the average values of the measurement as described by Bland-Altman 25, 26. Analyses were performed using SPSS 16.0.1 (SPSS Inc. Chicago IL). A two-sided p-value less than 0.05 was used to denote statistical significance.
 

RESULTS

Eight AL patients had New York Heart Association functional classification I, with 1 each presenting in Class III and IV heart failure. Left ventricular ejection fraction was 62.4├é┬▒0.6% in control subjects and 58.6├é┬▒2.8% for AL (p=NS) (Table 1). AL subjects had thicker anteroseptum, increased left atrial volume index and tendency towards increased left ventricular mass index. The lateral mitral annular velocity (E™) was 15.4├é┬▒9.2 cm/s and ratio of mitral inflow velocity to E™ (E/E™) was 7.2├é┬▒3.3 in AL subjects. Although E and E/E™ data were not available in control subjects, the mean values of E™ and E/E™ in AL subjects in addition to increased left atrial volume index are consistent with diastolic dysfunction and increased left ventricular filling pressures based on prior validation studies 27-30. Based on conventional evaluation of degree of diastolic dysfunction using mitral inflow and mitral annular velocity 31, 1 AL patient had normal diastolic function, 3 had mild (impaired relaxation pattern), 4 had moderate (pseudonormalization) and 2 had severe (restrictive) diastolic dysfunction.

There was higher 16-SD% in AL subjects compared to controls (Table 1, Figures 1-2, see Additional files 1-2). There was shorter cycle length in AL subjects compared to controls. There was no correlation between cycle length and 16-SD% (R=-0.2, p=NS). 16-SD% was weakly correlated with left ventricular mass index (R=0.45, p=0.04). There was no correlation between 16-SD% and left ventricular ejection fraction (R=-0.3, p=0.14).

Intraclass correlation coefficient was 0.625 (p=0.001) for intraobserver and 0.606 (p=0.002) for interobserver differences in 16-SD%. The ICC together with the Bland-Altman analysis (Figure 3) show good reproducibility of 16-SD% measurements. The Bland-Altman plot further shows better agreement in the measurement at lower 16-SD% values.

 

References
  1. Sanchorawala V, Wright DG, Seldin DC, Dember LM, Finn K, Falk RH, et al. An overview of the use of high-dose melphalan with autologous stem cell transplantation for the treatment of AL amyloidosis. Bone Marrow Transplant. 2001 Oct;28(7):637-42.
  2. Comenzo RL, Vosburgh E, Simms RW, Bergethon P, Sarnacki D, Finn K, et al. Dose-intensive melphalan with blood stem cell support for the treatment of AL amyloidosis: one-year follow-up in five patients. Blood. 1996 Oct 1;88(7):2801-6.
  3. Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol. 1995 Jan;32(1):45-59.
  4. Dispenzieri A, Gertz MA, Kyle RA, Lacy MQ, Burritt MF, Therneau TM, et al. Prognostication of survival using cardiac troponins and N-terminal pro-brain natriuretic peptide in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation. Blood. 2004 Sep 15;104(6):1881-7.
  5. Klein AL, Hatle LK, Burstow DJ, Seward JB, Kyle RA, Bailey KR, et al. Doppler characterization of left ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol. 1989 Apr;13(5):1017-26.
  6. Klein AL, Hatle LK, Taliercio CP, Taylor CL, Kyle RA, Bailey KR, et al. Serial Doppler echocardiographic follow-up of left ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol. 1990 Nov;16(5):1135-41.
  7. Koyama J, Davidoff R, Falk RH. Longitudinal myocardial velocity gradient derived from pulsed Doppler tissue imaging in AL amyloidosis: a sensitive indicator of systolic and diastolic dysfunction. J Am Soc Echocardiogr. 2004 Jan;17(1):36-44.
  8. Koyama J, Ray-Sequin PA, Davidoff R, Falk RH. Usefulness of pulsed tissue Doppler imaging for evaluating systolic and diastolic left ventricular function in patients with AL (primary) amyloidosis. Am J Cardiol. 2002 May 1;89(9):1067-71.
  9. Siqueira-Filho AG, Cunha CL, Tajik AJ, Seward JB, Schattenberg TT, Giuliani ER. M-mode and two-dimensional echocardiographic features in cardiac amyloidosis. Circulation. 1981 Jan;63(1):188-96.
  10. Ghio S, Constantin C, Klersy C, Serio A, Fontana A, Campana C, et al. Interventricular and intraventricular dyssynchrony are common in heart failure patients, regardless of QRS duration. Eur Heart J. 2004 Apr;25(7):571-8.
  11. Baker GH, Hlavacek AM, Chessa KS, Fleming DM, Shirali GS. Left ventricular dysfunction is associated with intraventricular dyssynchrony by 3-dimensional echocardiography in children. J Am Soc Echocardiogr. 2008 Mar;21(3):230-3.
  12. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005 Apr 14;352(15):1539-49.
  13. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, et al. Longer-term effects of cardiac resynchronization therapy on mortality in heart failure [the CArdiac REsynchronization-Heart Failure (CARE-HF) trial extension phase]. Eur Heart J. 2006 Aug;27(16):1928-32.
  14. Bellavia D, Pellikka PA, Abraham TP, Al-Zahrani G, Dispenzieri A, Oh J, et al. Hypersynchronization" by Tissue Velocity Imaging in Patients with Cardiac Amyloidosis. Heart (British Cardiac Society). 2008 May 12.
  15. Zeng X, Shu XH, Pan CZ, Chen RZ, Cheng K, Liu SZ, et al. Assessment of left ventricular systolic synchronicity by real-time three-dimensional echocardiography in patients with dilated cardiomyopathy. Chinese medical journal. 2006 Jun 5;119(11):919- 24.
  16. Maceira AM, Joshi J, Prasad SK, Moon JC, Perugini E, Harding I, et al. Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation. 2005 Jan 18;111(2):186-93.
  17. Vogelsberg H, Mahrholdt H, Deluigi CC, Yilmaz A, Kispert EM, Greulich S, et al. Cardiovascular magnetic resonance in clinically suspected cardiac amyloidosis: noninvasive imaging compared to endomyocardial biopsy. J Am Coll Cardiol. 2008 Mar 11;51(10):1022-30.
  18. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr. 1989 Sep-Oct;2(5):358-67.
  19. Kapetanakis S, Kearney MT, Siva A, Gall N, Cooklin M, Monaghan MJ. Realtime three-dimensional echocardiography: a novel technique to quantify global left ventricular mechanical dyssynchrony. Circulation. 2005 Aug 16;112(7):992-1000.
  20. Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol. 1986 Feb 15;57(6):450-8.
  21. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005 Dec;18(12):1440-63.
  22. Gottdiener JS, Bednarz J, Devereux R, Gardin J, Klein A, Manning WJ, et al. American Society of Echocardiography recommendations for use of echocardiography in clinical trials. J Am Soc Echocardiogr. 2004 Oct;17(10):1086-119.
  23. Sampat MP, Whitman GJ, Stephens TW, Broemeling LD, Heger NA, Bovik AC, et al. The reliability of measuring physical characteristics of spiculated masses on mammography. Br J Radiol. 2006 Dec;79 Spec No 2:S134-40.
  24. Rosner B. Fundamentals of biostatistics. Belmont, CA: Duxbury Press 2005.
  25. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet. 1986 Feb 8;1(8476):307-10.
  26. Bland JM, Altman DG. Applying the right statistics: analyses of measurement studies. Ultrasound Obstet Gynecol. 2003 Jul;22(1):85-93.
  27. Arques S, Roux E, Luccioni R. Current clinical applications of spectral tissue Doppler echocardiography (E/E' ratio) as a noninvasive surrogate for left ventricular diastolic pressures in the diagnosis of heart failure with preserved left ventricular systolic function. Cardiovascular ultrasound. 2007;5:16.
  28. Nagueh SF, Sun H, Kopelen HA, Middleton KJ, Khoury DS. Hemodynamic determinants of the mitral annulus diastolic velocities by tissue Doppler. J Am Coll Cardiol. 2001 Jan;37(1):278-85.
  29. Ommen SR, Nishimura RA, Appleton CP, Miller FA, Oh JK, Redfield MM, et al. Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: A comparative simultaneous Dopplercatheterization study. Circulation. 2000 Oct 10;102(15):1788-94.
  30. Sohn DW, Chai IH, Lee DJ, Kim HC, Kim HS, Oh BH, et al. Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol. 1997 Aug;30(2):474-80.
  31. Kirkpatrick JN, Vannan MA, Narula J, Lang RM. Echocardiography in heart failure: applications, utility, and new horizons. J Am Coll Cardiol. 2007 Jul 31;50(5):381- 96.
  32. Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med. 1997 Sep 25;337(13):898-909.
  33. Kyle RA, Bayrd ED. Amyloidosis: review of 236 cases. Medicine. 1975 Jul;54(4):271-99.
  34. Kyle RA, Greipp PR. Amyloidosis (AL). Clinical and laboratory features in 229 cases. Mayo Clinic proceedings. 1983 Oct;58(10):665-83.
  35. Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, et al. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med. 2004 Jan 20;140(2):85-93.
  36. Dubrey SW, Cha K, Anderson J, Chamarthi B, Reisinger J, Skinner M, et al. The clinical features of immunoglobulin light-chain (AL) amyloidosis with heart involvement. Qjm. 1998 Feb;91(2):141-57.
  37. Bleeker GB, Holman ER, Steendijk P, Boersma E, van der Wall EE, Schalij MJ, et al. Cardiac resynchronization therapy in patients with a narrow QRS complex. J Am Coll Cardiol. 2006 Dec 5;48(11):2243-50.
  38. Bleeker GB, Mollema SA, Holman ER, Van de Veire N, Ypenburg C, Boersma E, et al. Left ventricular resynchronization is mandatory for response to cardiac resynchronization therapy: analysis in patients with echocardiographic evidence of left ventricular dyssynchrony at baseline. Circulation. 2007 Sep 25;116(13):1440-8.
  39. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004 May 20;350(21):2140-50.
  40. Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation. 2005 Sep 27;112(13):2047-60.

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