There is a paucity of information regarding CRT implantation in patients with non-compaction cardiomyopathy and, when published, series are generally small. In addition, those published cases with implanted CRT were compared only to DCM and dyssynchrony was evaluated by echocardiography. As far as we know, this is the first work comparing non-compaction CM with ischemic and non-ischemic CM using gated-SPECT phase analysis to evaluate pre- and post-CRT intraventricular dyssynchrony.
In the present study we found that CRT contributes to a marked improvement in non-ischemic CM patients with non-compaction myocardium. We showed a functional improvement in all CM groups, but those more dyssynchronous at baseline (the ones with non-compaction CM) exhibited the more significant improvement on the intraventricular synchronism: PSD was reduced from 89.5±14.2 degrees at baseline to 63.7±20.5 degrees post-CRT (p=0.028). As we previously showed [22], a dyssynchrony reduction as measured by LV PSD could be associated with outcome improvement.
Gated-SPECT MPI contributes to the differentiation between ischemic and non-ischemic ventricular dysfunction. Ischemic -dysfunction usually causes diffuse, severe, and extensive perfusion defects and wall motion abnormalities in coronary artery distribution, whereas those with non-ischemic etiology have either homogeneous tracer uptake or mild to moderate perfusion defects in non-coronary artery distribution, as well as diffuse wall motion abnormalities [32,33]. This coincides with our results, where mean SRS was significantly higher for ischemic patients (14.9±7.1) vs. 9±3.9 (non-ischemic) and 8.7±4.4 (non-compaction CM patients), p<0.0001.
Although the quality of life (measured by the MLHFQ) significantly improved in all groups, which could also be mediated by placebo effect in some cases, non-ischemic patients (with or without non-compaction) showed a better functional improvement (objectively measured by LVEF increase and EDV and ESV reduction) at 6 months post-CRT.
Presence of baseline mechanical dyssynchrony measured by echo has been associated with a response to resynchronization therapy [34]. Delgado et al [14] found that baseline LV radial dyssynchrony, discordant LV lead position, and myocardial scar in the region of the LV pacing lead were independent determinants of long-term prognosis in ischemic HF patients treated with CRT. However, no potential marker of mechanical dyssynchrony reliably predicts response, and interobserver variability is an important drawback to consider, mainly if echocardiography is the imaging technique used. Gated-SPECT phase analysis is a useful and validated option to evaluate mechanical intraventricular dyssynchrony and predict post-CRT results [19,25,31,35]. In our previous work in the IAEA research project [22] all baseline and post-CRT studies were processed in a core lab. We found that the difference between baseline and six months post-CRT dyssynchrony is a sensitive parameter of clinical outcomes, rather than the baseline value by itself. Thus, LV dyssynchrony automatically measured by PSD from gated-SPECT MPI is a valid marker of CRT clinical outcomes.
In the present work we have found that CRT caused a reduction of the dyssynchrony measured through PSD and HBW in all groups. Nevertheless, those more dyssynchronous at baseline (the patients with non-compaction CM) exhibited the more significant improvement in the intraventricular synchronism: PSD was reduced from 89.5±14.2 degrees at baseline to 63.7±20.5 degrees post-CRT (p=0.028).
The activation of neurohormonal and cytokine systems during the progression of HF leads to alterations in myocyte biology, myocyte loss and alterations in extracellular matrix, as well as alterations in LV chamber geometry (LV remodeling) (), [36]. Thus, it is understandable that treatments which can revert this remodeling (as CRT) will originate a functional improvement, as we found among our cases, mainly in those with non-compaction CM.
Several authors [37-39] reported that SRS was an independent predictor of mechanical dyssynchrony, and this is plausible considering that infarcted and ischemic segments with WM abnormalities lead to an abnormal contraction pattern and dyssynchrony [40]. Compared to non-ischemic ones, our ischemic patients experienced more hard events: non-ischemic CM showed more heart failure admissions (5), but ischemic ones showed more deaths. Although the difference was not significant (this might be due to the small sample included), the ischemic group showed the lower number of responders (86%) compared to the non-ischemic (89%) and the non-compaction CM (100%). This coincides with other reports, where patients with non-ischemic cardiomyopathy respond more frequently than those with ischemic heart disease [41].
Although it has been reported that females have considerably higher response rates to CRT than males [41], we did not find the same. In fact, in our study there was no difference according to sex in the number of responders (89% among men vs. 88% among women) and we do not have a specific explanation for this.
Dyssynchrony and CRT outcome in non-compaction cardiomyopathy
Left ventricular non-compaction(or left ventricular hypertrabeculation) is a morphological abnormality of the left ventricular myocardium, characterised by a meshwork of myocardial strings, interlacing, and orderless in arrangement, most frequently located in the apex and the lateral wall. LVNC is believed to be congenital in the majority of cases, but may develop during life in single cases (acquired LVNC) [42]. The prevalence of adult LVNC ranges from 0.01% to 0.27% [43,44], and it is more frequent in men (about two-thirds) than women in the majority of the studies [42,43,45].
In LVNC patients, HF is primarily due to systolic dysfunction, and the leading symptom is dyspnea. Other common manifestations include arrhythmias such as ventricular tachycardia and atrial fibrillation, as well as systemic thromboembolic events. The most frequent electrocardiocardiographic abnormality is LBBB, reported in up to 56% of cases [43].
LVNC per se does not require a specific treatment. Adequate therapy is indicated only in case of complications, such as ventricular arrhythmias, cardioembolism, or systolic dysfunction. CRT is indicated in case of intractable HF despite optimal medical treatment, and mechanical dyssynchrony [46]. CRT has been applied in single LVNC patients and has shown a beneficial effect [26-28,42,47].
In our work, those patients with non-compaction CM showed the higher improvement both functionally and in terms of reduction of intraventricular dyssynchrony. All of them were responders to CRT. This coincides with the results of Bertini et al [28]. These authors compared the effects of CRT on LV reverse remodelling in 52 patients with DCM associated or not with isolated LVNC by using standard and contrast echocardiography to assess LV volumes and function and to optimise visualisation of the endocardial border at baseline and at 6 months’ follow-up. They concluded that patients with LVNC and CM had greater LV reverse remodelling after CRT than did patients with DCM. The greater the area of non-compaction (higher number of LVNC segments) the greater the chance of achieving CRT response and greater LV reverse remodelling [28].
It has been reported that dyssynchrony between non-compacted and compacted myocardium contributes to global LV dysfunction [4]. However, Bertini et al did not find differences in LV dyssynchrony between LVNC CM and DCM patients, although in the subset of LVNC CM patients, CRT achieved greater LV reverse remodelling and determined more super-responders than in patients with DCM [28]. We also analysed the intraventricular dyssynchrony behavior by using phase analysis gated-SPECT, which constitutes the novelty of our work in comparison with previously published papers on CRT on LVNC patients. In contrast with Bertini’s paper, we did find higher intraventricular dyssynchrony in LVNC patients compared to those with DCM, and its reduction by CRT may contribute to the higher functional improvement observed in these LVNC patients. The fact of considering the higher reproducibility of nuclear measurements compared to other imaging techniques (as echo) may represent an added value in the clinical management of LVNC patients.
Interestingly, Bertini et al [28] indicated that their data seem in agreement with the hypothesis that LVNC is part of a more widespread cardiomyopathy, involving both the morphologically normal and the dysmorphic segments, and that, in particular, the LVNC segments may represent a phenotypic expression of this disease that may be partially or totally reversible. Indeed, in a single case with neuromuscular disorder, Stöllberger et al reported a complete regression of LVNC areas after CRT [48]. This represents a thought-provoking phenomenon which should be more thoroughly studied.
On the other hand, it has been reported that LVNC segments have, paradoxically, a better performance than morphologically normal ones [49]. In their work, Bertini et al hypothesized that, according to this, and taking into account that the LV lead is positioned in a (postero-)lateral vein tributary of LVNC areas in the majority of patients, pacing LVNC segments may provide beneficial effects on LV function, partially explaining the larger percentage of super-responders they found as compared with patients with DCM [28]. In our case, this explanation seems possible as well, because in 82% of our LVNC patients the LV lead was positioned in the lateral wall.
Limitation
A small sample of patients was included, mainly of those who had a non-compaction CM. Anyway, this condition is not frequent, and we also offer the information regarding the intraventricular dyssynchrony by using gated-SPECT phase analysis, which can be considered as an added value.