1. University Medical Center Groningen, The Netherlands
Simultaneous Atrial and Ventricular Reverse Remodeling in Patients receiving Cardiac Resynchronization Therapy
Mariëlle Kloosterman, Michiel Rienstra, MD, Bart A. Mulder, MD, Isabelle C. Van Gelder, MD, Alexander H. Maass, MD.
University Medical Center Groningen, The Netherlands

2. Overview Background Heart Failure Cardiac Resynchronization Therapy
Reverse Remodeling
Aim
Methods & Definitions
Results
Conclusions
Q&A

3. Watchlearnlive – American Heart Association ®
Heart Failure
Approximately 2% of the adult population in developed countries has HF; most patients will be aged .70 years and about half will have an LVEF ,50%.
Heart failure can be defined as an abnormality of cardiac structure or function leading to failure of the heart to deliver
oxygen at a rate that is sufficient with the requirements of the metabolizing tissues.
Clinically, HF is defined as a syndrome in which patients have typical symptoms (e.g.
breathlessness, ankle swelling, and fatigue) and signs (e.g. elevated jugular venous pressure, pulmonary crackles, and displaced
apex beat) resulting from an abnormality of cardiac structure or function.
Underlying cardiac is usually myocardial disease causing systolic ventricular dysfunction. However, abnormalities
of ventricular diastolic function or of the valves, pericardium, endocardium, heart rhythm, and conduction can also cause
HF (and more than one abnormality can be present)
Watchlearnlive – American Heart Association ®

4. Left bundle branch block
Sinus node AV
node
Stimulation therapy
Conduction block
Sinus node AV
node
Conduction block
Both inter- and intra-ventricular conduction delays lead to asynchronous contraction
of LV wall regions (ventricular dyssynchrony), impairing cardiac efficiency and reducing stroke volume and systolic blood
pressure. Poorly coordinated papillary muscle function may cause or aggravate functional systolic mitral regurgitation. Impaired performance promotes adverse LV remodelling.
Cardiac resynchronization therapy helps to restore AV, inter- and intra-ventricular synchrony.

5. Electrical (dys)synchrony
Mechanical dyssynchrony occurs secondary to electrical dyssynchrony [left bundle branch block (LBBB)], which is corrected by cardiac resynchronization therapy. Colours indicate areas of early (red) to late (blue) activation of the ventricles
After sensing the arrhythmia, the CRT device sends signals through the same leads to ‘’resynchronize’’ ventricular contractions, or in other words, make the ventrciular contract at the same time.
This leads to:
Intraventricular Activation
Organized ventricular activation sequence
Coordinated septal and free-wall contraction
Improved pumping efficiency
So it improves LV function and induces LV reverse remodelling.
Steffel J.and Leclercq C. Eur Heart J. 2014;35:13-15.

6. Reverse Remodeling Left ventricular reverse remodeling
reduction of left ventricular end systolic volume of ≥ 15% after six months
In patients with LV systolic dysfunction, the maladaptive changes occurring in surviving myocytes and extracellular matrix after myocardial injury (e.g. myocardial infarction) lead to pathological ‘remodelling’ of the ventricle with dilatation and impaired
contractility, one measure of which is a reduced EF.11,20 What characterizes untreated systolic dysfunction is progressive worsening
of these changes over time, with increasing enlargement of the left ventricle and decline in EF, even though the patient may be
symptomless initially.
The limited cardiac reserve of such patients is also dependent on atrial contraction, synchronized contraction of the left ventricle,
and a normal interaction between the right and left ventricles. Intercurrent events affecting any of these [e.g. the development
of AF or conduction abnormalities, such as left bundle branch block (LBBB)] can lead to acute decompensation.
Drakos S.G., Khoury A.G., Stehlik J. et al. Circulation.2012;126:

7. Randomised Controlled Trials
Studies (n randomized)
Year
MUSTIC SR (58)
2001
MIRACLE (453)
2002
PATH CHF (41)
MUSTIC-AF (59)
MIRACLE-ICD (369)
2003
CONTAK CD (490)
PATH-CHF II (86)
COMPANION (1520)
2004
MIRACLE-ICD II (186)
CARE-HF (814)
2006
REVERSE (610)
2008
MADIT-CRT (1820)
2009
RAFT (1798)
2010
Effects of CRT
↓ NYHA Class
↑ Quality of Life Score
Exercise Capacity
↑6 minute walking distance
↑Peak VO2
LV function
↑ Ejection Fraction
↓Mitral regurgitation
Reverse Remodeling (± 60%)
↓ LVESV
↓ Heart Failure Hospitalizations
↓ Mortality
LVEF <35%, QRS >120 ms and LBBB.
Functional NYHA class II, III despite optimal medical treatment.
NYHA = New York Heart Association, LV = left ventricular;
LVESV = left ventricular end systolic volume

8. Aim However..The effect of (simultaneous) left atrial reverse
remodeling has not been adequately evaluated
Aim
Explore the prognostic effect of atrial reverse remodeling on all-cause mortality or heart failure hospitalizations during CRT in patients with atrial fibrillation (AF) or sinus rhythm.
Left atrial volume is independendent predictor of outcome (survival and major adverse cardiovascular events) in HF patients, independent of LV geometry.
Møller J.E., Hillis G.S., Oh J.K., et al. Circulation.2003;107:

9. Methods & Definitions Methods
Single-center, retrospective, observational study
365 patients receiving a CRT(-D)
Primary outcome
composite endpoint of all-cause mortality and heart failure hospitalizations
Definition of response
Ventricular reverse remodeling - a reduction of LVESV of ≥15% after 6 months
Atrial reverse remodeling - a reduction of left atrial volume index (LAVI) of ≥10%* after 6 months
*Additional analyses with LAVI reduction >0%, ≥ 5%, and ≥15%.

10. Left Atrial Volume Index (LAVI) (ml/m²)
Biplane method of discs (modified Simpson's rule)
When left atrial (LA) size is measured clinically, LA volume determinations are preferred over linear measurements since they allow more accurate assessment of the asymmetric remodeling of the LA chamber. Moreover, the strength of the relationship between cardiovascular diseases is stronger for LA volume than for LA linear dimensions.
Max. LA area in apical 4 chamber view and maximal LA area in apical 2-chamber view.
L = length measured from back wall to line across mitral hinge points.
Image: Lang R.M., Bierig M., Devereux R.B., et al. Eur Heart J Cardiovasc Imaging.2006;

11. Degree of atrial and ventricular (reverse) remodeling
LAVI = left atrial volume index; LVESV = left ventricular end systolic volume

12. Results - Baseline characteristics
Atrial and ventricular reverse remodeling
(n=76)
Only ventricular reverse remodeling
(n=125)
Only atrial reverse remodeling
(n=40)
No atrial and ventricular reverse remodeling
(n=124)
p-value for trend
Age – yr – mean±SD
65.4 ±11.0
65.0±11.2
61.9±11.4
66.0±10.7
0.23
Male sex – no. (%)
52 (68)
92 (74)
30 (75)
94 (76)
0.71
History of AF – no. (%)
23 (30)
54 (43)
11 (28)
56 (45)
0.06
Ischaemic cardiomyopathy – no. (%)
33 (43)
55 (44)
18 (45)
68 (55)
0.27
NYHA class– (%)
0.59
II / III / IV
34 / 65 / 1
40 / 55 / 5
40 / 57 / 3
31 / 64 / 5
Electrocardiogram
Heart rate – mean±SD –bpm
74±17
75±15
77±12
75±13
0.69
QRS duration -mean±SD- ms
166±24
160±26
162±22
153±24
0.006
Echocardiographic parameters
LV end systolic volume – mean ± SD–ml
190±91
184±83
171±95
155±69
0.01
Left atrial volume index – mean ±SD – ml/m2
44±17
40±21
45±14
43±19
0.39
LV ejection fraction - mean ±SD - %
24±10
24±9
22±8
25±10
0.221
AF = atrial fibrillation; bmp = beats per minute; LV = left ventricular; NYHA = New York Heart Association; SD = standard deviation

13. Determinants of atrial- and ventricular reverse remodeling
Multivariate analysis
Atrial reverse remodeling
Ventricular reverse remodeling
OR (95% CI)
p-value
QRS duration (per 10 ms increase)
1.14 ( )
0.012
LVESV (per 25 ml increase)
1.17 ( )
<0.001
Left atrial length (per 5 ml increase)
0.84 ( )
0.002
Mitral regurgitation
2.1 ( )
0.007
History of AF
0.56 ( )
0.039
Ischemic cardiomyopathy (CAD or MI)
0.64 ( )
0.050
AF = atrial fibrillation; CAD = coronary artery disease; CI = confidence interval; LVESV = left ventricular end systolic volume; MI = myocardial infarction;
OR = odds ratio

14. Atrial Fibrillation Burden
AF Burden 6 months – tertiles - %
Atrial and ventricular reverse remodelling
(n=24)
Only
ventricular reverse remodelling
(n=53)
atrial
reverse remodelling
(n=16)
No atrial and ventricular reverse remodelling
(n=58)
p-value
for trend
<2%
5 (21)
20 (38)
6 (38)
14 (24)
2-99.9%
13 (54)
9 (17)
9 (56)
22 (38)
100%
6 (25)
24 (45)
1 (6)
0.005

15. All-cause mortality or heart failure hospitalizations
Mean follow-up: 2.0 ± 1.0 years
49 patients died (19 with AF)
24 patients were hospitalized

16. Multivariate Cox Regression models
Atrial and ventricular reverse remodelling versus no atrial and ventricular reverse remodelling
All-cause mortality or
heart failure hospitalisations
HR (95% CI)
p-value
Atrial reverse remodelling ≥10% reduction
Model 1
Model 2
Model 3
3.3 ( )
3.1 ( )
3.1 ( )
0.007
0.01
HR= hazard ratio; CI = confidence interval
Model 1 - not adjusted
Model 2 - adjusted for gender and age at implantation
Model 3 - adjusted for gender, age at implantation, mitral regurgitation,
ischemic cardiomyopathy, and atrial fibrillation.

17. Explanation?  Diastolic filling
Atrial reverse remodelling in the absence of ventricular reverse remodelling might be explained by improvement in diastolic filling. Although the importance of AV synchrony is unquestioned, the need for routine, systematic AV delay optimisation in all patients undergoing CRT remains controversial even though haemodynamic studies have demonstrated the importance of AV delay on cardiac function in the context of CRT.
AV delay too long (E/A fusion and diastolic MR). AV delay too short (A wave truncation)
E = early component of LV filling A = atrial component of LV filling

18. Atrio-ventricular interval optimisation
E = early component
of LV filling
A = atrial component
These patients with prolonged / shortened AV conduction appear to derive benefit from echo-guided AV delay optimisation due to improvement of diastolic dysfunction.
The transmitral flow profiles observed in the group with only atrial reverse remodelling (n=40) A) Fusion of E and A wave at baseline resulting in diastolic dysfunction which had disappeared at 6 month follow up B) Truncation of the A wave of mitral inflow at baseline resulting in delayed left atrial contraction after closure of the mitral valve that had disappeared at 6 month follow up. C) Normal mitral inflow that is not improved by AV optimisation or reverse remodelling. AV opt. = Atrioventricular optimisation; FU = follow up.
These results suggest the importance of AV interval optimisation in patients with fusion of E and A wave or truncation of the A wave of mitral inflow at baseline, even if no desirable effect of CRT on the left ventricle can be observed.

19. Conclusions
There is discordance in atrial and ventricular reverse remodelling in a significant number of patients who receive CRT
The event free survival of patients with only atrial reverse remodelling did not significantly differ compared to patients with both atrial and ventricular reverse remodelling
Adverse atrial and ventricular remodelling seems to be an important contributor to a worse outcome in patients receiving CRT
Ventricular reverse remodelling should not merely be the focus in assessing outcome after CRT. Atrial reverse remodelling may provide additional prognostic information
a decrease in left ventricle size can be accompanied by an increase in left atrial size, just as that an increase in left ventricle size can be accompanied by a decrease in left atrial size.

20. Thank you for your attention

21. Q&A