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

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

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 ®

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.

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.

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;126:2230-241.

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

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;107:2207-2212.

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%.

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;79-108.

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

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

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 (1.03-1.27) 0.012 LVESV (per 25 ml increase) 1.17 (1.08-1.26) <0.001 Left atrial length (per 5 ml increase) 0.84 (0.75-0.94) 0.002 Mitral regurgitation 2.1 (1.23-3.68) 0.007 History of AF 0.56 (0.32-0.97) 0.039 Ischemic cardiomyopathy (CAD or MI) 0.64 (0.41-1.0) 0.050 AF = atrial fibrillation; CAD = coronary artery disease; CI = confidence interval; LVESV = left ventricular end systolic volume; MI = myocardial infarction; OR = odds ratio

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

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

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 (1.4-8.0) 3.1 (1.3-7.5) 3.1 (1.3-7.6) 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.

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

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.

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.

Thank you for your attention

Q&A