New insight into device therapy for chronic heart failure
Ypenburg, C.
Citation
Ypenburg, C. (2008, October 30). New insight into device therapy for chronic heart failure. Retrieved from https://hdl.handle.net/1887/13210
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C h a p t e r 6
Effect of total scar burden on contrast-enhanced magnetic resonance imaging on response to cardiac resynchronization therapy
Claudia Ypenburg Stijntje D. Roes Gabe B. Bleeker
Theodorus A.M. Kaandorp Albert de Roos
Martin J. Schalij Ernst E. van der Wall Jeroen J. Bax
Am J Cardiol 2007;99:657-60
ABSTRACT
It has been demonstrated that improvement in left ventricular (LV) function and reverse remodeling after cardiac resynchronization therapy (CRT) were greater in patients with non- ischemic cardiomyopathy than in patients with ischemic cardiomyopathy. The aim of this study was therefore to evaluate the influence of scar burden on response to CRT. We included 34 patients with ischemic cardiomyopathy (New York Heart Association class 3.1±0.4, LV ejection fraction 23±7%). Contrast-enhanced magnetic resonance imaging (MRI) was used to determine the total scar burden, using a 17-segment model with a 5-point hyperenhancement scale (from score 0= no hyperenhancement indicating no scar, to score 4= hyperenhancement
>76%, transmural scar). Linear regression analysis showed a significant correlation (r=-0.91, P<0.05) between the total scar burden at baseline and the change in LV end-systolic volume after 6 months of CRT. Also, patients not responding to CRT had significantly more scar tissue than responders. In fact, a scar burden of >1.20 resulted in complete functional non-response.
In conclusion, total scar burden, as assessed with contrast-enhanced MRI is an important factor influencing response to CRT and may be included in the selection process for CRT candidates.
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INTRODUCTION
Recently, Bleeker et al suggested that, besides the presence of left ventricular (LV) dyssynchrony, transmural scar tissue in the region of the LV pacing lead may prohibit functional and clinical response to cardiac resynchronization therapy (CRT) (1). Furthermore, Woo et al demonstrated that reverse remodeling and improvement in LV ejection fraction (EF) after CRT were larger in non-ischemic patients than in ischemic patients (2). This may imply that not only the location but also the size of infarcted myocardium (total scar burden) is important for response to CRT. One could anticipate that in patients with a large extent of scar tissue, improvement in LV function after CRT will be limited, even if the region of the LV pacing lead is viable. The current study evaluates the importance of the total scar burden for functional response to CRT.
Contrast-enhanced magnetic resonance imaging (MRI) was used to determine the extent and transmurality of the scar tissue.
METHODS
Patients, study protocol
A total of 34 consecutive patients with ischemic cardiomyopathy who were scheduled for CRT implantation were prospectively enrolled in this study. Fifteen patients were included in a previous study (1). The traditional selection criteria for CRT were used: New York Heart Association (NYHA) class III or IV, LVEF <35% and QRS duration >120 ms. Ischemic etiology was based on the presence of significant coronary artery disease (>50% stenosis in one or more of the major epicardial coronary arteries) on coronary angiography and/or a history of myocardial infarction, prior percutaneous coronary intervention or coronary artery bypass graft surgery. None of the patients had a recent myocardial infarction (<3 months) or presented with decompensated heart failure. Patients with pacemakers or intracranial clips were excluded.
The study protocol included contrast-enhanced MRI to determine the extent and transmurality of infarcted myocardial tissue (total scar burden) before CRT implantation. Furthermore, clinical status was assessed and resting 2-dimensional transthoracic echocardiography was performed to measure LV volumes and LVEF before implantation. Clinical status and echocardiographic parameters were re-assessed after 6 months of CRT to determine response to CRT.
Magnetic resonance imaging, data acquisition and analysis
A 1.5-Tesla Gyroscan ACS-NT MRI scanner (Philips Medical Systems, Best, the Netherlands) equipped with powertrack 6000 gradients was used. Patients were positioned in a supine position and images were acquired during breathholds of approximately 15 seconds. The heart was imaged from apex to base (3), with 10 to 12 imaging levels (dependant on the heart size) in the short axis view using a sensitivity encoding, balanced fast-field echo sequence.
Contrast-enhanced images were acquired 17 to 19 minutes after bolus injection of gadolinium diethylenetriamine penta-acetetic acid (Magnevist, Shering/Berlex, Berlin, Germany; 0.15 mmol/kg) with an inversion-recovery gradient echocardiographic sequence; the inversion time was determined with a real-time scan plan. Depending on the patient’s heart rate and heart
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size, 20 to 24 slices were obtained in 2 breathhold acquisitions of approximately 15 seconds.
The following parameters were applied: 400 x 400 mm² field of view, 256 x 256 matrix size, a 5 mm slice thickness, slice gap of -5 mm, 15º flip angle, echo time of 1.36 ms, and 4.53 ms repetition time (4).
The contrast-enhancement images were scored visually by two experienced observers (blinded to all other data) according to a previously described 17-segment model (5). Segmental scar score was appointed with 0=absence of hyperenhancement, 1=hyperenhancement of 1% to 25% of LV wall thickness, 2=hyperenhancement extending 26% to 50%, 3=hyperenhancement extending 51% to 76%, and 4=hyperenhancement extending 76% to 100% (4). The number of affected segments was considered to reflect the spatial extent of scar tissue. The number of segments with a segmental scar score of 3 and 4 was considered to reflect the transmurality of scar tissue in the infarct zone. Patients’ segmental scores were summed and divided by 17 to yield the total total scar burden (which reflected the damage per patient). Reproducibility for visual analysis was reported in a previous study; the inter- and intraobserver variability were 4.2±6.6% and 3.0±5.1% respectively (6).
Echocardiography, data Acquisition and analysis
Baseline and follow-up examinations were performed in the left lateral decubitus position using a commercially available system (Vingmed Vivid Seven, General Electric-Vingmed, Milwaukee, Wisconsin, USA). Images were obtained using a 3.5 MHz transducer, at a depth of 16 cm in the parasternal and apical views (standard long-axis and 2- and 4-chamber images). Standard 2-dimensional and color Doppler data, triggered to the QRS complex were saved in cine-loop format. LV end-diastolic (EDV) and end-systolic volumes (ESV) were derived and LVEF was calculated from the conventional apical 2- and 4-chamber images, using the biplane Simpson’s technique (7). Inter- and intra-observer variability for the assessment of LVEF and LV volumes was 90% and 96% respectively.
The severity of mitral regurgitation was graded semi-quantitatively from color-flow Doppler images using the apical 4-chamber views. Mitral regurgitation was graded on a 4-point scale:
mild=1+ (jet area/left atrial area <10%), moderate=2+ (jet area/left atrial area 10-20%), moderately severe =3+ (jet area/left atrial area 20-45%), and severe=4+ (jet area/left atrial area >45%) (8).
Clinical evaluation
Evaluation of clinical status was performed at baseline and after 6 months of follow-up by an independent physician blinded to all other data. The clinical parameters included NYHA class, quality-of-life score (using the Minnesota Living with Heart Failure questionnaire) and 6-minute walking distance (9,10). In all patients, QRS duration was measured from the surface electrocardiogram using the widest QRS complex from the leads II, V1 and V6.
Device implantation
First, a coronary sinus venogram was obtained using balloon catheter, followed by the insertion of the LV pacing lead. An 8F guiding catheter was used to guide the LV lead (Easytrak 4512-80, Guidant Corporation, St. Paul, Minnesota; or Attain-SD 4189, Medtronic Inc., Minneapolis, Minnesota) into the coronary sinus. The preferred position was a lateral or postero-lateral vein (11). The right atrial and ventricular leads were positioned conventionally. All leads were
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connected to a dual chamber biventricular ICD (Contak CD or TR, Guidant Corporation; or Insync III or CD, Medtronic Inc.)
Statistical analysis
Results are expressed as mean ± SD. Comparison of data was performed using the paired and unpaired Students t test for continuous variables and Fisher’s exact test for proportions.
Linear regression analysis was performed to evaluate the relation between the magnitude of LV reverse remodeling (reduction in LVESV) after 6 months of CRT and total scar burden, spatial extent, and transmurality respectively. For all tests, a P-value <0.05 was considered statistically significant.
RESULTS
Study population
Baseline characteristics are listed in Table 1. Device implantation was successful in all patients and no procedure-related complications were observed. Two patients died of worsening heart failure before the 6-month follow-up evaluation.
Total scar burden
Of the 578 segments evaluated, 329 (57%) showed no hyperenhancement (score 0), 68 (12%) showed minimal hyperenhancement (score 1), and 63 (11%) had hyperenhancement
Table 1. Patient characteristics (n=34)
Age (yrs) 68±10
Gender (M/F) 29/5
NYHA class 3.1±0.4
QRS duration (ms) 152±36
LBBB 21 (62%)
Sinus rhythm 29 (85%)
LV dyssynchrony (ms) 85±37
LVEF (%) 23±7
LVEDV (ml) 228±77
LVESV (ml) 180±72
Grade 3-4+ mitral regurgitation 6 (18%)
Medication
Diuretics 33 (97%)
ACE-inhibitors 28 (82%)
Beta-blockers 22 (65%)
Spironolactone 14 (41%)
Digoxin 8 (24%)
ACE: angiotensin-converting enzyme; EDV: end-diastolic volume; EF: ejection fraction; ESV: end-systolic volume; LBBB: left bundle branch block; LV: left ventricular; NYHA: New York Heart Association.
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score 2, 64 (11%) had score 3, and 54 (9%) score 4. Accordingly, 118 segments showed transmural scar tissue (score 3 and 4) and mean transmurality (number of segments with score 3 or 4) per patient was 3.4±2.5. The number of segments with any hyperenhancement (spatial extent) ranged from 0 to 14 per patient (mean 7.3±3.5).
Extensive regions of scar tissue were present as indicated by a total scar burden of 1.0±0.6 (ranging from 0 to 2.12).
Response to CRT
After 6 months of CRT, mean NYHA class had decreased from 3.1±0.4 to 2.4±0.8 (P<0.01).
In addition, the 6-minute walking distance improved from 299±97 m to 350±132 m (P<0.01). Also, symptoms improved as evidenced by the significant decrease in quality-of-life score of 32% on average (from 41±14 to 28±19, P<0.01). Echocardiographic evaluation after 6 months of CRT showed significant reverse remodeling; LVESV decreased from 180±72 ml to 150±57 ml (P<0.01). Also, the LVEDV decreased from 227±77 ml at baseline to 208±63 ml after 6 months of CRT (P<0.01). LVEF was 23±7%
at baseline and improved significantly at 6 months follow-up to 28±9% (P<0.01).
On the basis of an improvement of ≥10%
in LVESV (12), 18 patients (53%) were classified as responders and 16 (47%) as non- responders. The patients who died before 6 months follow-up were classified as non- responders. Baseline characteristics were comparable between responders and non- responders, except that QRS duration was less in the non-responders (167±34 ms vs.
135±31 ms, P<0.05) and non-responders had significantly smaller LV volumes (Table 2).
After 6 months of CRT, responders showed a significant improvement in clinical parameters after CRT, whereas none of the clinical parameters improved in the non-responders (Table 3). In addition, an Figure 1. Relationship between the percentage
change in LV end-systolic volume (LVESV) after 6 months of CRT and the total scar burden (A), spatial extent (B), and transmurality (C) at baseline
0,00 0,50 1,00 1,50 2,00
Total scar burden -40
-20 0 20 40 60 80
Change in LVESV (%)
y = -0.4369 x + 0.550 r = 0.91, P < 0.05
0 2 4 6 8 10 12 14
Spatial extent (segments) -40
-20 0 20 40 60 80
Change in LVESV (%)
y = -0.0551 x + 0.52 r = 0.78, P < 0.05
0 2 4 6 8
Transmurality (segments) -40
-20 0 20 40 60 80
Change in LVESV (%)
y = -0.0935 x + 0.4274 r = 0.90, P < 0.05
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improvement in LVEF with reverse remodeling was noted in the responders after CRT; these effects were not observed in the non-responders.
Total scar burden and response to CRT
Linear regression analysis showed a significant inverse relation between the total scar burden and reverse remodeling, defined as the relative change of LVESV after 6 months of CRT (Figure 1A, r=-0.91, P<0.05); the more scar burden the less reverse remodeling. Also, the spatial extent and transmurality were correlated with a change in LVESV (Figures 1B and C).
Furthermore, patients not responding to CRT had significantly more scar tissue than responders, as demonstrated by significantly higher spatial extent, transmurality and total scar burden
Table 2. Echocardiographic and MRI findings at baseline in responders (n=18) and non-responders (n=16)
Responders Non-responders P-value
LVEF (%) 22±6 24±7 NS
LVEDV (ml) 253±92 198±44 <0.05
LVESV (ml) 205±84 152±43 <0.05
Spatial extent (No. of segments with any hyperenhancement) 5.1±3.0 9.8±2.2 <0.05 Transmurality (No. of segments with hyperenhancement
score 3 or 4)
1.6±1.5 5.6±1.6 <0.05
Total scar burden (Summation of individual segmental hyperenhancement scores)
0.6±0.4 1.5±0.3 <0.05
Abbreviations as in Table 1.
Table 3. Clinical and functional improvement (Δ) in CRT responders and non-responders
Responders Non-responders P-value
Δ NYHA class 1.1±0.7 0.1±0.5 <0.05
Δ Quality-of-life score 21±19 4±10 <0.05
Δ 6-minute walking distance (m) 100±100 7±102 <0.05
Δ LVEF (%) 9±7 -1±5 <0.05
Δ LVEDV (%) -16±19 8±12 <0.05
Δ LVESV (%) -31±14 9±12 <0.05
Abbreviations as in Table 1.
Figure 2. Relation between total scar burden (categorized) and response to CRT. A score >1.20 will result in functional non-response
0.00-0.30 0.30-0.60 0.60-0.90 0.90-1.20 1.20-1.50 1.50-1.80 1.80-2.10 0
25 50 75 100
Responders Non-responders
Total scar burden
Percentage
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Scar burden and response to CRTC H A P T E R 6
(Table 2). In fact, none of the patients with a total scar burden >1.20 had responded to CRT (Figure 2).
DISCUSSION
The results of the current study in ischemic heart failure patients demonstrate that the total scar burden, as assessed with contrast-enhanced MRI, is an important factor influencing response to CRT; the more extensive the scar burden, the lower the likelihood of LV reverse remodeling after CRT.
Currently, data about infarct size and response to CRT are scarce. Only one study by Hummel et al evaluated the relation between viability and response to CRT using contrast echocardiography (13). A perfusion score index, reflecting the extent of viable myocardium, was related to LV reverse remodeling (defined as a reduction LV end-diastolic dimension) after 6 months (P=0.003, r=-0.68), indicating that the more viable myocardium present, the larger the reverse remodeling. This observation is in line with the findings in the current study; the total scar burden was linearly related to the relative change in LVESV after 6 months of CRT (Figure 1A). Also, the spatial extent and transmurality of scar tissue showed strong relations (r=-0.78 and r=-0.90 respectively, both P<0.05) with echocardiographic improvement during follow-up (Figures 1B and C).
Furthermore, the present study demonstrated that echocardiographic responders to CRT (reduction in LVESV ≥10%) had a significantly smaller total scar burden as compared to non- responders (0.6±0.4 vs. 1.5±0.3, P<0.05). Figure 2 indicates that a total scar burden >1.20 will result in non-response to CRT in terms of LV reverse remodeling. Also, Hummel et al demonstrated that the patients with lower perfusion score index (less viable segments) tended to have less clinical improvement (13). Still, future larger studies are needed to identify the precise cut-off value for the total scar burden beyond which response of CRT will not occur.
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REFERENCES
1. Bleeker GB, Kaandorp TA, Lamb HJ et al. Effect of posterolateral scar tissue on clinical and echocardio- graphic improvement after cardiac resynchronization therapy. Circulation 2006;113:969-76.
2. Woo GW, Petersen-Stejskal S, Johnson JW et al. Ventricular reverse remodeling and 6-month outcomes in patients receiving cardiac resynchronization therapy: analysis of the MIRACLE study. J Interv Card Electro- physiol 2005;12:107-13.
3. Lamb HJ, Doornbos J, van der Velde EA et al. Echo planar MRI of the heart on a standard system: valida- tion of measurements of left ventricular function and mass. J Comput Assist Tomogr 1996;20:942-9.
4. Kaandorp TA, Bax JJ, Schuijf JD et al. Head-to-head comparison between contrast-enhanced magnetic resonance imaging and dobutamine magnetic resonance imaging in men with ischemic cardiomyopathy.
Am J Cardiol 2004;93:1461-4.
5. Cerqueira MD, Weissman NJ, Dilsizian V et al. Standardized myocardial segmentation and nomencla- ture for tomographic imaging of the heart: a statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation 2002;105:539-42.
6. Schuijf JD, Kaandorp TA, Lamb HJ et al. Quantification of myocardial infarct size and transmurality by contrast-enhanced magnetic resonance imaging in men. Am J Cardiol 2004;94:284-8.
7. Schiller NB, Shah PM, Crawford M et al. Recommendations for quantitation of the left ventricle by two- dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcom- mittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 1989;2:358-67.
8. Thomas JD. How leaky is that mitral valve? Simplified Doppler methods to measure regurgitant orifice area. Circulation 1997;95:548-50.
9. Rector TS, Kubo SH, Cohn JN. Validity of the Minnesota Living with Heart Failure questionnaire as a measure of therapeutic response to enalapril or placebo. Am J Cardiol 1993;71:1106-7.
10. Lipkin DP, Scriven AJ, Crake T et al. Six minute walking test for assessing exercise capacity in chronic heart failure. Br Med J (Clin Res Ed) 1986;292:653-5.
11. Alonso C, Leclercq C, Victor F et al. Electrocardiographic predictive factors of long-term clinical improve- ment with multisite biventricular pacing in advanced heart failure. Am J Cardiol 1999;84:1417-21.
12. Yu CM, Bleeker GB, Fung JW et al. Left ventricular reverse remodeling but not clinical improvement predicts long-term survival after cardiac resynchronization therapy. Circulation 2005;112:1580-6.
13. Hummel JP, Lindner JR, Belcik JT et al. Extent of myocardial viability predicts response to biventricular pacing in ischemic cardiomyopathy. Heart Rhythm 2005;2:1211-7.
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