Cardiac Resynchronisation Therapy: How to Identify Patients Who Will not Respond to Therapy

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Who Will not Respond to Therapy

M.M. GULIZIA, A. RAGUSA, G.M. FRANCESE

Congestive heart failure (CHF) is the major cause of mortality, morbidity, and hospitalisation in patients aged ≥ 60 years in Europe and the USA, with a prevalence in this latter from 0.4% up to 2% [1]. In addition to the clinical symptoms such as left ventricular dysfunction, reduced exercise tolerance, and impaired quality of life, these patients often have a markedly shortened life expectancy, with a further worsening in those with heart conduction defects [2–5]. Despite major advances in medical therapy [6-16], mortality and morbidity remain still high [17].

Cardiac resynchronisation therapy (CRT) was introduced in the early 1990s [18]. It was approved by the FDA in 2001 and was classified in the American College of Cardiolog y/American Heart Association/North American Society of Pacing and Electrophysiology/Heart Rhythm Society 2002 guideline update for the implantation of pacemaker and anti-arrhyth- mic devices with evidence level IIA [19] for patients with idiopathic or ischaemic cardiomyopathy and severe heart failure (NYHA functional class III or IV) despite optimised medical therapy, with left ventricular ejection fraction < 35%, QRS duration > 120 ms, and left ventricular end-diastolic diameter > 55 mm. These guidelines were based on two controlled trials:

Multisite Stimulation in Cardiomyopathy (MUSTIC) [20] with a crossover design and Multicenter InSync Randomised Clinical Evaluation (MIRACLE) [21] a parallel placebo trial.

The results of MUSTIC [20], PATH-CHF (Pacing Therapies for Congestive Heart Failure study) [22, 23], and the preliminary data from the Italian InSync Registry (InSIR) [24, 25] demonstrated the enhancing effect of car-

Cardiology Department, S. Luigi – S. Currò Hospital, Catania, Italy

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diac resynchronisation therapy (CRT) on heart haemodynamic performance, working ability, and quality of life in a large number of patients with CHF and uncoordinated contraction, but while the majority of patients ‘feel better’ with CRT and the benefit has an On-Off effect (COMPANION study) [26–31], still 20–30% of patients did not respond to CRT, emphasising the need for additional selection criteria to identify potential responders [32].

Table 1 shows the proposed patient selection of the major studies on CRT. All the studies reported in this table demonstrated a statistical (P <

0.001) improvement in mean NYHA class in the biventricular paced popula- tion, as well as an increase (P < 0.001) in the mean distance walked in 6 min (with the exception, for this latter, of the Contak ICD Trial). All these studies also showed an improvement in the quality of life of the patients by a reduction of more than 30% of the Minnesota Living with Heart Failure test score, but no definite indication has been given towards finding any clinical routine-practice predictors that would identify patients who will or will not respond to CRT.

Table 1.Proposed patient selection of the major studies on CRT

Study (number NYHA QRS Sinus ICD Status

randomised)^a class

MUSTIC AF (43) III > 200b AF No Published

PACMAN (328) III ≥ 150 Normal No Enrolled

MUSTIC SR (58) III > 150 Normal No Published

VecToR (420) II,IV ≥ 140 Normal No Published

MIRACLE (453) III,IV ≥ 130 Normal No Published

MIRACLE ICD (369) III,IV ≥ 130 Normal Yes Published

MIRACLE ICD II (186) II ≥ 130 Normal Yes Published

CARE HF (800)c III,IV ≥ 120 Normal Y/N Published

COMPANION (>1600) III, IV ≥ 120 Normal Y/N Published

CONTAK CD (227) III,IV ≥ 120 Normal Yes Published

PATH-CHF (41) III,IV ≥ 120 Normal No Published

PATH-CHF II (89) III,IV ≥ 120 Normal No Published

aEF ≤ 35% for all

bRV paced QRS

cEcho-based criteria for < 150 ms

QRS QRS duration at standard electrocardiogram, Sinus patients in sinus rhythm (normal) or atrial fibrillation (AF), ICD biventricular ICD device implantation

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At present, although no definite guideline has been given about the selection of patients who will or will not respond to CRT, recent data from many authors’ studies may provide indications and clinical routine-practice predictors that can identify patients who will respond to CRT.

Leclerq et al. [33] identified a clinical predictive parameter in the LVEF (P < 0.036) and an acute predictive one when an increase was recorded in cardiac output and a decrease in PCWP by more than 10% during DDD BiV pacing compared to baseline AAI mode.

In another study, Kass et al. [34] demonstrated the positive correlation existing between the baseline QRS duration and the dP/dtmax during left ventricle and BiV pacing. However, because of some discrepancies in the response to BiV pacing observed in some patients with wide QRS, authors postulate that finding the optimal pacing site can play a major role in CRT.

The same results were found by Auricchio et al. [35], who underlined the importance of a baseline QRS duration > 150 ms, which was able to identify most of the responders to BiV pacing.

To determine whether some factors could predict the long-term clinical effectiveness of CRT, Alonso et al. [36] studied 26 patients with drug-refractory heart failure and wide QRS implanted with a BiV pacemaker. NYHA class, exercise tolerance, and LVEF were recorded at baseline and after pacemaker implantation. Patients were divided into two groups: group I, responders; group II, non-responders. QRS duration and axis at baseline and during BiV pacing, interventricular conduction time, and left and right ventricular lead positions were compared between the two groups. Only QRS duration during BiV pacing differed between the two groups, with a significantly shorter value in group I than in group II (154 ± 17 ms vs 177 ± 26 ms; P

= 0.016).

In a study on the sensitivity and specificity of QRS duration in predicting the acute benefit in CHF patients (PATH-CHF I and II) treated with CRT, Kadhiresan et al. [37] demonstrated that at smaller QRS duration thresholds the specificity tends to be lower, while accuracy was highest (80%) at a QRS duration of 155 ms, with positive and negative predictive values of 77% and 92% respectively.

Performing cardiac catheterisation in 22 CHF patients with a dual-sensor micromanometer to measure LV and aortic pressure during sinus rhythm and LV free wall pacing, Nelson et al. [38] demonstrated that, although mechanical dyssynchrony is a key predictor for pacing efficacy in CHF patients with conduction delay, combining information about QRS and basal dP/dtmaxprovides an excellent tool by which to identify maximal responders.

Other authors [39], speculating on the idea that pacing two sites with the longest conduction delay will result in the largest improvement in cardiac function in CHF, demonstrated that applying CRT in these sites does not

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necessarily produce better haemodynamic improvement in CHF patients.

Some authors [40] have hypothesised that the percentage increase in QRS duration at short atrioventricular delays during BiV pacing can distinguish responder from non-responder sites, while others [41] have demonstrated, in a group of 18 CHF patients in atrial fibrillation treated with BiV pacing compared to a group of 56 in sinus rhythm, that CRT improved both patient groups, suggesting that inter- and intraventricular resynchronisation had a more important effect than atrioventricular delay optimisation.

In partial contrast with these just-mentioned results, in the analysis of 54/316 patients enrolled in the InSIR [42], LVEDD was the only significant predictor of clinical outcome. The authors postulate that this could be due to the poor contractility reserve of a very dilated left ventricle, as shown by the LVEF percentage increasing only in the responders group.

The recent studies have suggested the role of assessing systolic asynchrony to predict improvement of systolic function or LV reverse remodelling [43–49] [defined as a reduction of left ventricle end systolic volume (LVESV)] > 15% 3 months after CRT, while the non-responders are defined by a reduction of LVESV ≤ 15%). Mechanical dyssynchrony is not necessarily related to electrical dyssynchrony, and the presence of substantial left ventricular dyssynchrony is a major predictor of response to CRT. Indeed, the absence or lesser extent of ventricular dyssynchrony can identify non- responders to CRT. Moreover, many patients with a wide QRS complex do not exhibit LV dyssynchrony, whereas many patients with a narrow QRS complex may demonstrate LV dyssynchrony. These considerations suggest that electrocardiography is not an accurate marker of electromechanical delay, as electrical delay may not occur in patients with left bundle branch block, whereas significant mechanical asynchrony is absent in nearly 30% of patients with prolonged QRS duration [50]. Thus, many investigators are looking for any features that will predict the clinical response in the individ- ual patient who is the optimal candidate for CRT but did not respond to CRT.

NYHA functional class IV, marked dilatation of the left ventricle (DTD >

60 mm), severe mitral regurgitation, an unstable haemodynamic status, and a VTI of aortic flow ≤ 12 cm are considered to be associated to a negative response to CRT [51]. Furthermore, many authors have suggested that the likelihood of responding to CRT is lower in patients with ischaemic heart disease, sustained ventricular tachycardia, and severe mitral regurgitation [52], whereas others have demonstrated that the percentages of responders to CRT were comparable in the group of patients with ischaemic disease and in those with idiopathic cardiomyopathy, underlining that the aetiology of heart failure was not related to the response to CRT [53].

Given the limitations of surface ECG, the authors in the CARE-HF study proposed some echocardiographic parameters to investigate the presence of

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ventricular dyssynchrony [54, 55]. Thus, in patients with a QRS duration of 120–150 ms it is possible to evaluate the presence of ventricular dyssynchrony by the presence of the following echocardiographic parameters: (1) a prolonged aortic pre-ejection delay (> 140 ms), (2) an increased mechanical interventricular delay (> 40 ms), and (3) a left ventricular segmental postsystolic contraction (LVPSC).

The first echocardiographic parameter is derived from the measurement between the onset of the QRS complex and the beginning of the aortic flow on pulsed-wave Doppler imaging. The second echocardiographic parameter can be evaluated by assessing the extent of interventricular mechanical delay, defined as the time difference between the onset of the pulmonary and the aortic flow (left and right ventricular pre-ejection intervals = IVMD) during pulsed-wave Doppler imaging. An IVMD ≥ 40 ms is considered indicative of interventricular dyssynchrony, and in the MIRACLE trial this index was reduced by 19% after CRT. Finally, LVPSC is defined as the maximal local wall inward movement occurring later than the start of the trans- mitral Doppler flow signal.

The prolongation of the delay of the first two parameters just cited results in a decrease in left ventricular contraction duration and a decrease in regional ejection fraction. Moreover, Yu et al. [55] using tissue Doppler imaging (TDI) found a large mechanical delay between the free right ventricular wall and the lateral wall of the left ventricle, which was completely reversed after CRT. So, as described by other authors [56], a simple rule can be repre- sented by: the longer the aortic pre-ejection delay, and the shorter the left ventricular filling duration, the more advanced the ventricular dyssynchrony. However, besides the interventricular dyssynchrony, which is defined as an asynchronous right–left ventricular contraction and relaxation occurring in left bundle branch block patients that produces abnormal septal motion with a reduced interventricular septal contribution to global left ventricular performance, there are other forms of asynchrony that may contribute to ventricular dyssynchrony [57].

Briefly, the atrioventricular dyssynchrony is an abnormal conduction of the AV node which results in: a delay between atrial and ventricular contraction; mitral valve incompetence with occurrence of late diastolic regurgitation; shortened ventricular filling time, limiting diastolic stroke volume; and, often, immediate occurrence of atrial systole with early passive filling, hence reducing left ventricular filling. In this case left ventricular performance can be improved by adequate atrioventricular timing. It has been proposed that the optimal atrioventricular delay should provide the longest left ventricular filling time without premature truncation of the A-wave by mitral valve closure. This approach is widely accepted as a simple method by which to optimise atrioventricular delay, although it is not clear whether atrioventricular

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timing optimisation is needed or whether an atrioventricular delay of 100 or 120 ms would be appropriate for all patients.

At present attention is focused on the intraventricular dyssynchrony as data revealing that a lower degree of intraventricular dyssynchrony results in a lower benefit from CRT. It occurs when a portion of the left ventricle is prematurely activated and generates regions of both early and delayed contraction that will contribute to altered LV performance [51]. Using M-mode echocardiography, Pitzalis et al. [43] demonstrated that a septal-to-posterior wall motion delay (SPWMD) ≥ 130 ms was a marker of intraventricular dyssynchrony. However, the SPWMD cannot be obtained, either because the septum is akinetic after extensive anterior infarction or because the maximal posterior motion is not defined. In addition, it is often not possible to obtain a perpendicular M-mode section of the proximal left ventricle. TDI can provide accurate information about intraventricular dyssynchrony by assessing peak systolic velocity at different regions of the myocardium and the timing of peak systolic velocity. Bax et al. [46] measured intraventricular dyssynchrony by placing two sample volumes on the basal parts of the septum and lateral wall, and a delay ≥ 60 ms, referred as septal-to-lateral delay, was an indicator of substantial intraventricular dyssynchrony. Yu et al. [50] used TDI to assess intraventricular dyssynchrony into 12 myocardial segments.

For each segment the time from onset of QRS complex to peak systolic velocity was measured and two parameters were obtained: the maximal difference between peak systolic velocities of any 2 of the 12 segments (intraventricular dyssynchrony defined as difference > 100 ms) and the SD of all 12 time intervals measuring time to peak systolic velocity (dyssynchrony index SD >

33 ms) Only patients with an index > 33 ms demonstrated reverse remodelling after CRT. More recently, Yu et al. [49] utilised tissue synchronisation imaging (TSI), a parametric imaging derived from 2D TDI which automati- cally calculates and colour-codes the time to peak tissue velocity in every position in the image with reference to QRS signal, using the six basal mid- segmental model. The cut-off of the SD of the peak systolic velocities of the LV segments was 34.4 ms. The commonest site of most severe delay was the inferior wall (45%), followed by the lateral wall (30%), posterior wall (25%), septal wall (16%), and anteroseptal wall (5%). However, only the presence of lateral wall delay at baseline was associated with a reverse remodelling response (sensitivity 47%, specificity 89%) [49, 57]. Therefore a simple algorithm could be used to identify responders or non-responders to CRT in which the combination of these two parameters, lateral wall delay and SD >

34.4 ms, gave a specificity of 87% and a sensitivity of 82% (Fig. 1). Ansalone et al. [45] have also shown that the most delayed wall was the lateral one (35%), while the inferior wall and the septum infrequently show the latest mechanical activity; furthermore, these authors demonstrated that biven-

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tricular pacing provided additional benefit when applied at the most delayed site. A limitation of TDI with velocity imaging is its inability to determine whether the motion represents contraction or is merely passive. Strain and strain rate allows direct assessment of the degree of myocardial deformation during systole; strain is expressed as the percentage of segmental shortening or lengthening in relation to the original length, while strain rate measures the rate of local deformation. Compared with TDI, strain rate differentiates better between active systolic contraction and passive displacement, which is of particular importance in ischaemic patients with scar tissue [58]. Tissue tracking and strain rate imaging have also proved useful in assessing longitudinal resynchronisation. The latter is interpreted as a decrease in percentage of the extent of LV basal segments displaying delayed longitudinal contraction (an active contraction after closure of the aortic valve), and CRT reduced the extent of this form of diastolic contraction. Sogaard et al. [47]

focused on late or postsystolic longitudinal contraction at the base of the left ventricle, and delayed longitudinal contraction is considered a superior pre- Fig. 1.Suggested algorithm for assessing systolic asynchrony by tissue synchronisation imaging (TSI) to identify responders and non-responders to cardiac resynchronisation therapy and predict reverse remodelling (modified from [49]). 2D two dimensional, SD standard deviation

Qualitative TSI of 2D images in ejection phase, at apical 4-chamber, 2-chamber and long axis views

Most severe or equally severe delay at lateral wall

Likely responders to CRT

Proceed to quantitative TSI:

Ts-SD-12-ejection

Likely non-responders to CRT

>34.4 ms

<34.4 ms Yes

No

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dictor of CRT (less extensive mechanical asynchrony, less response to CRT).

In conclusion, cardiac resynchronisation therapy (CRT) is now considered an established therapy for patients with heart failure, with good clinical results, although 20–30% do not respond. Many investigators are looking for reliable predictors of patient response to CRT. Although no definite guideline has been given as of today about the selection of patients who will or will not respond to CRT, recent data from many authors’ studies may provide indications and clinical routine-practice predictors that can identify patients.

At present, several echocardiographic methods to assess dyssynchrony have been proposed, varying from conventional to advanced approaches, pri- marily involving TDI, trans thoracic (TT), TSI, strain, and strain rate. It cur- rently unclear which of these parameters provides optimal information on dyssynchrony and which parameters may actually allow prospective identifi- cation of responders and non-responders to CRT. However, based on the assessment of AV, interventricular, and intraventricular dyssynchrony, accurate prediction of response to CRT will be feasible. In particular TDI may allow precise assessment of intra-and interventricular dyssynchrony and could be included in the selection of candidates for CRT. Moreover, based on the assessment of the site of latest activation in LV, echocardiography can guide LV lead positioning and may be used to optimise AV delay and V-V delay.

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