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Original article
Effects of cardiac resynchronisation therapy on dilated cardiomyopathy with isolated ventricular non-compaction
  1. Matteo Bertini,
  2. Matteo Ziacchi,
  3. Mauro Biffi,
  4. Elena Biagini,
  5. Guido Rocchi,
  6. Cristian Martignani,
  7. Marinella Ferlito,
  8. Ferdinando Pasquale,
  9. Elena Cervi,
  10. Angelo Branzi,
  11. Claudio Rapezzi,
  12. Giuseppe Boriani
  1. Department of Cardiology, University of Bologna, Bologna, Italy
  1. Correspondence to Dr Matteo Bertini, Department of Cardiology, University of Bologna, Massarenti 9, 40138 Bologna, Italy; doc.matber{at}gmail.com

Abstract

Objective To compare the effects of cardiac resynchronisation therapy (CRT) on left ventricular (LV) reverse remodelling in patients with dilated cardiomyopathy (DCM) associated or not with isolated ventricular non-compaction (IVNC).

Methods and results 52 patients with heart failure, candidates for CRT, were recruited: 20 patients with IVNC associated with DCM (IVNC-DCM) without other coexisting cardiac diseases and 32 patients with DCM without IVNC matched for age, gender, body surface area and LV systolic function. Standard and contrast echocardiography were used to assess LV volumes and function and to optimise visualisation of the endocardial border at baseline and at 6 months' follow-up. Patients with heart failure were subsequently classified as CRT negative responders, non-responders, responders or super-responders based on different LV reverse remodelling 6 months after CRT implantation. Different types of CRT response were observed in IVNC-DCM and DCM patients. In particular, in IVNC-DCM patients the percentage of super-responders was significantly higher than for patients with DCM (60% vs 28%, respectively, p=0.023). In addition, the number of IVNC segments had a trend towards reduction with respect to baseline (4 (3–6)) at 6 months' follow-up (3 (1–5); p=0.067). Finally, in IVNC-DCM, the patients with a higher number of IVNC segments at baseline (>4) were more likely to be responders or super-responders than patients with ≤4 IVNC segments (p=0.003).

Conclusions Patients with IVNC-DCM had greater LV reverse remodelling after CRT than patients with DCM. The greater the area of non-compaction (higher number of IVNC segments) the greater the chance of achieving CRT response and greater LV reverse remodelling.

  • Implantable cardioverter defibrillator (ICD)
  • echocardiography-contrast
  • cardiomyopathy dilated
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Introduction

Cardiac resynchronisation therapy (CRT) has been shown to improve left ventricular (LV) systolic performance, morbidity and mortality in patients with heart failure.1–3 The beneficial effects of CRT on LV reverse remodelling and systolic function are particularly pronounced in the subgroup of patients with dilated cardiomyopathy without coronary artery disease (DCM).4 5 Isolated ventricular non-compaction (IVNC) is emerging as a particular myocardial morphological abnormality still in search of a nosographic identity.6 7 Although it can be observed in otherwise normal hearts and in association with all the main types of cardiomyopathy (including hypertrophic, restrictive and right ventricular arrythmogenic dysplasia), IVNC is most commonly found in association with a DCM (IVNC-DCM).6 8 9

Thus far, little is known about the effects of CRT in IVNC-DCM patients.10 11 In particular, whether the benefits of CRT in IVNC-DCM are similar to those in patients with DCM still remains obscure, since only case reports or very small case series have been reported to date.10–12

This study aimed to compare the effect of CRT on clinical and echocardiographic parameters in IVNC-DCM and DCM patients. The specific impact of CRT on IVNC areas is also described. Finally, the possible impact of the amount of IVNC myocardium on CRT response was analysed.

Patients and methods

Patient population and protocol

The study population consisted of 52 patients with heart failure without coronary artery disease who were candidates for CRT. Inclusion criteria were: sinus rhythm, LV ejection fraction (LVEF) ≤35%, and QRS complex duration ≥120 ms. In particular, 20 patients with heart failure had IVNC-DCM without other coexisting cardiac diseases (all patients with DCM associated with neuromuscular disorders were excluded). The remaining 32 patients with heart failure had DCM without IVNC. Importantly, patients with DCM without IVNC were matched for age, gender, body surface area and LV systolic function with the IVNC-DCM patients and were used as a comparison group. The study protocol included (1) evaluation of clinical status: New York Heart Association (NYHA) functional class, 6 min walking test13 at baseline and 6 months after CRT; (2) standard and contrast echocardiography at baseline and 6 months after CRT.

Echocardiography

All patients were imaged in the left lateral position using a commercially available system, Philips Sonos 5500 Ultrasound System (Philips Ultrasound, Andover, Massachusetts, USA), equipped with a harmonic fusion imaging probe (s3) and offline cineloop analysis software. All images were recorded digitally and analysed offline: each parameter was measured on the average of three consecutive beats.

Specific echocardiographic diagnostic criteria were used to define IVNC-DCM: (1) an excessively thickened myocardial wall with a two-layered structure comprising a thin compacted layer on the epicardial side and a much thicker non-compacted layer of prominent trabeculations and deep intertrabecular recesses on the endocardial side; (2) a non-compacted/compacted myocardium thickness ratio >2, as measured at the site of maximal thickness at the end-systolic phase of the cardiac cycle (figure 1); (3) colour-Doppler evidence that the deep intertrabecular recesses were in communication with the ventricular cavity. Contrast echocardiography was used in all the patients to clarify diagnostic ambiguities and optimise visualisation of the endocardial border; contrast echocardiography was also repeated 6 months after CRT implantation.6 9 14 The location of IVNC in the left ventricle was identified by dividing the left ventricle into 16 segments according to the American Society of Echocardiography guidelines (figure 1).15 LV volumes and LVEF were calculated according to the American Society of Echocardiography guidelines using contrast-enhanced echocardiographic images.15 Patients with heart failure were subsequently classified as CRT negative responders, non-responders, responders or super-responders according to the literature.16 17 Negative responders showed an increase of LV end-systolic volume at 6 months' follow-up, whereas non-responders, responders and super-responders showed a reduction of between 0% and 14%, between 15% and 29% and ≥30% of the LV end-systolic volume (LVESV) 6 months after CRT implantation, respectively.16 17 Mitral regurgitation was quantified by the colour-area method.15 Finally, LV dyssynchrony was assessed using tissue Doppler imaging calculating septal to lateral delay, as previously described.18

Figure 1

Example of patients with dilated cardiomyopathy and isolated left ventricular (LV) non-compaction (IVNC) segments in apical posterolateral segments. (A) Apical LV four-chamber view without (left side) and with (right side) contrast-echocardiography. Arrows show IVNC segments in the apical region. (B) Apical LV three-chamber view without (left side) and with (right side) contrast-echocardiography. Arrows show IVNC segments in the posterior region. (C) Biplane fluoroscopy illustrating the position of the right atrial (RA) lead, right ventricular (RV) lead and LV lead in the right anterior oblique (RAO) and left anterior oblique (LAO) views. The RA and RV leads were placed in conventional sites (right atrial appendage and right ventricular apex, respectively). Interestingly, the LV lead was placed in the posterolateral vein in an apical position matching the IVNC segments. Of note, this patient was a super-responder at 6 months' follow-up.

The reproducibility of LVESV and LVEF of our echo laboratory has been reported in a previous study.19

CRT implantation

All patients gave written informed consent and received a biventricular pacemaker with cardioverter-defibrillator function (Contak Renewal 4RF, Boston Scientific St Paul, Minnesota; or InSync III Marquis, or Concerto Medtronic, Minneapolis, Minnesota).

Target veins were lateral or posterolateral coronary veins. The LV lead position was determined using biplane fluoroscopy classification.20 The left anterior oblique and the right anterior oblique views made it possible to identify the site (anterolateral or posterolateral) and the distance from the LV apex (mid-to-apex or mid-to-base) of the LV lead placement (figure 1).20

Statistical analysis

Continuous data are presented as median and IQR (25th–75th centile). Categorical variables are presented as frequencies and percentages, and were compared using χ2 test with Yates' correction. Mann–Whitney U test was used to compare two groups of unpaired continuous variables. Data within patient groups were compared by Wilcoxon signed rank test or McNemar χ2 test as appropriate. A two-tailed p value of <0.05 was considered significant. All statistical analyses were performed using SPSS for Windows (SPSS Inc), version 15.

Results

Patient population

Baseline characteristics of the study population are reported in table 1. In particular, the 6 min walking test value was significantly lower in IVNC-DCM than in patients with DCM (p=0.016), whereas, by definition, age, gender and NYHA functional class were not significantly different between the two groups. According to the matching selection process, no differences were seen in LV volumes and LVEF between IVNC-DCM and DCM patients. Eventually, the percentage of patients with severe mitral regurgitation was also similar and no significant differences were seen in LV dyssynchrony in the two groups. In all the patients with DCM with and without IVNC, the LV lead was positioned in a (postero-)lateral vein.

Table 1

Baseline characteristics of the IVNC-DCM and DCM patients

Clinical and echocardiographic effects of CRT in IVNC-DCM and DCM patients

The improvement in the 6 min walking test was greater (more pronounced) in IVNC-DCM patients than in patients with DCM (15.2 m (7.3–31.9) vs 10.2 m (3.2–16.9), p=0.046), whereas no significant differences were observed in NYHA functional class (p=0.70).

LV reverse remodelling, defined as a significant reduction of LVESV, was seen in both groups at 6 months' follow-up (table 2). However, the reduction of LV volumes at 6 months' follow-up (delta LV volumes) was greater for IVNC-DCM patients than for patients with DCM (table 2). Interestingly, different types of CRT response were seen in IVNC-DCM and DCM. In particular, in IVNC-DCM the number of negative responders, non-responders, responders and super-responders was 3 (15%), 3 (15%), 2 (10%) and 12 (60%), respectively; whereas in DCM the number of negative responders, non-responders, responders and super-responders was 10 (31%), 2 (6%), 11 (35%) and 9 (28%), respectively (figure 2). Interestingly, in IVNC-DCM patients the percentage of super-responders was significantly higher than in patients with DCM (60% vs 28%, respectively, p=0.023; figure 2).

Table 2

IVNC-DCM and DCM: standard echocardiographic variables at baseline and 6 months after cardiac resynchronization therapy

Figure 2

Distribution of the different types of response to cardiac resynchronisation therapy based on left ventricular end-systolic volume (LVESV) reduction in dilated cardiomyopathy (DCM) with isolated left ventricular non-compaction (IVNC-DCM) and without isolated left ventricular non-compaction (DCM). In IVNC-DCM, in particular, the percentage of super-responders was significantly higher than for DCM (60% vs 28%, respectively, p=0.023).

LV morphology in IVNC-DCM patients and CRT

At baseline, 89 LV segments were defined as IVNC. Specifically, 54 (60%) of IVNC segments were located in posterolateral wall, whereas only seven (8%) of IVNC segments were located in anterior wall or anteroseptum (figure 3). Interestingly, as mentioned above, all LV leads were placed in posterolateral veins matching most of the IVNC areas, as in the example in figure 1.

Figure 3

Distribution of isolated ventricular non-compaction in left ventricular walls. IVS, interventricular septum.

The number of IVNC segments in IVNC-DCM patients had a trend towards reduction with respect to baseline (4 (3–6)) at 6 months' follow-up (3 (1–5); p=0.067). On the other hand, dichotomising the IVNC-DCM patients based on the median number of IVNC segments at baseline, the patients with a higher number of IVNC segments at baseline (>4) were more likely to be responders or super-responders than patients with ≤4 IVNC segments (p=0.003; figure 4).

Figure 4

Distribution of response to cardiac resynchronization therapy between patients with dilated cardiomyopathy and ≤4 or >4 isolated ventricular non-compacted (IVNC) segments.

Discussion

This study evaluated the differences in CRT effects on IVNC-DCM and DCM patients. The main findings can be summarised as follows: (1) CRT has beneficial effects on LV volumes of IVNC-DCM patients, as the number of super-responders is significantly greater than for patients with DCM without IVNC segments; (2) the greater the number of IVNC segments (>4) at baseline, the greater the LV reverse remodelling after CRT.

Thus far, the beneficial effects of CRT on clinical and echocardiographic end points in DCM are well established. IVNC is generally encountered in association with DCM. However, the nosography of IVNC is debated and this condition is provisionally considered to be an ‘unclassified’ cardiomyopathy.7 9 Indeed it is unclear whether IVNC is a distinct cardiomyopathy, a subtype of DCM, a morphogenetic disorder, or an acquired condition (possibly derived from incomplete hypertrophy, cavity dilatation, metabolic defects or compensatory hypervascularisation).7 9 This study provides potentially important information for both clinical decision-making for IVNC-DCM patients and for a better understanding of the pathophysiology of this myocardial disease.

Clinical implications

This is the first study to examine the role of CRT in a relevant number of IVNC-DCM patients, and to look for a comparison with matched “conventional” patients with DCM.

Although no differences were found in LV dyssynchrony between IVNC-DCM and DCM patients, in the subset of IVNC-DCM patients, CRT achieved greater LV reverse remodelling determining more super-responders than in patients with DCM. Therefore, these findings show that CRT has positive effects in IVNC-DCM patients, and may also have a substantial impact on LV volume reduction.

Previously, preliminary observations from case reports or small case series had suggested possible beneficial effects of CRT in IVNC-DCM patients, 10–12 which is confirmed by this study.

Pathophysiological implications

In this study, a reciprocal link between IVNC areas and CRT was observed. From a ‘morphological’ point of view, a partial regression of IVNC areas was observed after 6 months of CRT, although not statistically significant as compared with baseline. From the “mechanical” point of view, those patients with more IVNC areas (>4 IVNC segments) were more likely to be CRT responders.

The partial regression of IVNC areas induced by CRT was not statistically significant (p=0.067), probably owing to the small number of patients or to the only partial effect of CRT on this morphology. This fact would support the theory that IVNC is a phenotypic marker of cardiac dysfunction. In particular, hypertrabeculation might be a compensatory mechanism activated by the failing ventricle in some areas to increase its energetic supply. Previously, it was reported that in IVNC-DCM disease the non-compacted segments had, paradoxically, a better performance than morphologically normal ones.14 Therefore, our data and the previous findings seem in agreement with the hypothesis that IVNC is part of a more widespread cardiomyopathy, involving both the morphologically normal and the dysmorphic segments. In particular, the IVNC segments may represent a phenotypic expression of this disease that may be partially or totally reversible. Indeed, in a single case with neuromuscular disorder, Stollberger et al reported a complete regression of IVNC areas after CRT.12

On the other hand, our study also provided important observations on LV morphology at baseline in IVNC-DCM patients. The LV lead was positioned in a (postero-)lateral vein tributary of IVNC areas in the majority of the patients. As previously mentioned, IVNC segments had, paradoxically, a better performance than morphologically normal ones.14 Therefore, pacing IVNC segments may provide beneficial effects for LV function, partially explaining the larger percentage of super-responders as compared with patients with DCM.

Intriguingly, the patients with >4 IVNC segments in the left ventricle had more LV reverse remodelling 6 months after CRT. This finding further supports the theory that IVNC represents areas with better performance as compared with the rest of the myocardium, more likely to improve when paced through the epicardial LV lead. Therefore, the greater the extent of these areas (more cardiac tissue available for resynchronisation), the greater the chance to achieve LV reverse remodelling after CRT. Interestingly, in a different population of patients, Bax et al21 reported that patients with more than four viable segments had better outcome after revascularisation. In our study, patients with more than four IVNC segments showed the better CRT response. These findings underline that the amount of viable myocardium amenable for resynchronisation is crucial in order to predict the response to treatment.

Conclusions

Patients with IVNC-DCM had greater LV reverse remodelling after CRT than patients with DCM. The greater the area of non-compaction (higher number of IVNC segments) the greater the chance of achieving CRT response and greater LV reverse remodelling.

References

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Footnotes

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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