Effects of late, repetitive remote ischaemic conditioning on myocardial strain in patients with acute myocardial infarction

The decline in mortality following ST-segment elevation myocardial infarction (STEMI) is mirrored by an increasing number of survivors with residual heart failure, a condition whose prognosis has not improved significantly in the last two decades [43, 57]. Therefore, key goals in combating ischaemic heart failure include (1) the early identification of at-risk individuals and (2) the development of effective strategies to limit adverse left ventricular (LV) remodelling.

Remote ischaemic conditioning (RIC) is a non-invasive cardioprotective strategy delivered through serial, short-lived periods of ischaemia–reperfusion in a tissue bed remote from the heart [19, 22, 40]. In some previous studies undertaken during the acute phase of STEMI, adjunctive RIC (with primary percutaneous coronary intervention [P-PCI]) attenuated infarct size and/or reduced the incidence of LV systolic dysfunction and major adverse cardiac events, albeit not consistently [1, 5, 9, 14, 31, 32, 42, 56, 60]. However, in the largest-scale randomised trial (CONDI-2/ERIC-PPCI, n = 5401), RIC failed to reduce infarct size or improve 12 month clinical outcomes (cardiac mortality/heart failure hospitalisation) [13, 18].

It has been suggested that a multi-targeted approach combining RIC with postconditioning immediately after stenting may afford greater cardioprotection [6, 8, 50]. Animal studies have also shown that late, repetitive ‘chronic’ remote ischaemic conditioning (CRIC) may mitigate against adverse LV remodelling [55]. We carried out the first randomised clinical trial evaluating CRIC (commencing on the third day following successful P-PCI and administered daily for 4 weeks) [51]. However, cardiovascular magnetic resonance (CMR) demonstrated no effect of CRIC on infarct size or global volumetric indices. Although CRIC commenced late after infarction may not be expected to impact infarct size, it may influence cardiac remodelling: hence, in this post-hoc analysis, we evaluated regional cardiac function as determined by myocardial strain imaging.

Our study was based on a non-specified post-hoc analysis of 73 STEMI patients recruited in the multicentre, prospective randomised Daily Remote Ischaemic Conditioning Following Acute Myocardial Infarction (DREAM) trial, assessing the impact of CRIC on LV systolic function. Trial design and methodology are as previously reported [51]. All subjects studied in the main trial were included in this post-hoc analysis. In brief, the trial comprised patients presenting to 4 P-PCI centres with a first STEMI successfully treated with P-PCI and baseline LVEF < 45% (determined by echocardiography). Participants were randomised in a 1:1 ratio (stratified by age, gender and infarct location) to 4 weeks’ duration of CRIC or sham treatment, beginning on the third day post-MI and self-administered at participants’ homes using the autoRIC^® Device (CellAegis Devices Inc, Toronto, Canada). The device was applied to the upper arm and for CRIC, the device delivered four 5 min cycles of inflation at 200 mmHg separated by 5 min of deflation between each cycle [total treatment time 35 min]; in the control group, the sham device employed the same cycle durations with inflation to 10 mmHg. In both groups during inflation, the device made identical vibrating noises, and participants were not told of the level of inflation required to deliver active treatment and whether they were in the control group. Participants were instructed to apply the device at the same time of day and on the same arm. Participants were asked to keep a diary of use of the device and were removed from the trial if they returned an incomplete diary sheet, missed more than three treatment sessions or missed more than two consecutive days of treatments. Written informed consent was obtained from each patient prior to enrolment. The study was approved by the regional ethics committee (12/EM/0304) and registered with clinicaltrials.gov (NCT01664611). It was conducted according to the principles of Good Clinical Practice and according to the Declaration of Helsinki, under the oversight of the University of Leicester.

This post-hoc analysis of the DREAM trial reveals that although CRIC does not alter infarct size or global LV indices (volumetry/strain), it is associated with altered regional strain in infarct-related and remote territories. The use of CRIC was associated with improvement in longitudinal strain in infarcted territories and an attenuated increase of circumferential strain in both infarcted and remote territories.

It remains unclear what underlies the disappointing failure to translate promising pre-clinical/early-phase clinical findings into hard clinical endpoints: potential reasons are extensively discussed in the literature.[20, 21, 23, 30] Interspecies differences mean that animal models may not fully replicate infarction in humans: whereas animal models utilise young, healthy animals, human disease is characterised by chronic atherosclerosis and the influence of risk factors such as diabetes, hypertension and hyperlipidaemia. Outcomes in clinical trials may be confounded by the influence of medications which can interfere with cardioprotection (e.g. P2Y purinoceptor 12 inhibitors or glyceryl trinitrate) or influence healing and remodelling independent of infarct size reduction (e.g. angiotensin-converting enzyme inhibitors and angiotensin II-receptor blockers).[17] Furthermore, improvements in reperfusion therapy (producing better and faster recanalisation) to attenuate infarct size and adjuvant pharmacotherapies to limit adverse remodelling may be so effective that no additional intervention with RIC may impact clinical outcome. Pre-infarct angina may also afford cardioprotection through the development of coronary collaterals or through a preconditioning-like effect. To date, most clinical studies have been small-scale and statistically underpowered, using surrogate measures rather than hard clinical endpoints. Even in the CONDI-2/ERIC-PPCI trial (n=5401), the utility of RIC may also have been limited by favourable patient factors (short symptom-to-PPCI time [median 3 hour] and spontaneous recanalisation at admission [TIMI 2-3 flow] in approximately 20% of participants). Greater benefit may be seen with RIC in higher risk patients, such as those with heart failure or large anterior infarcts [36].Another potential confounder is variation in the conditioned tissue mass: RIC administered to a leg may provide a greater stimulus than on a forearm: in a murine model, dual hindlimb RIC [with a greater mass of ischaemic/reperfused tissue] led to greater cardioprotection than single hindlimb RIC [33]. Similarly, a clinical trial utilising lower limb RIC demonstrated robust reduction in cardiac mortality and heart failure hospitalisation in contrast with many trials utilising forearm RIC which have failed to demonstrate clinical benefit [14]. However, another murine model found that one and two hindlimb preconditioning were equally protective, and a randomised clinical trial involving lower limb remote ischaemic per/postconditioning in 93 patients with anterior STEMI demonstrated no difference in myocardial salvage index or infarct size [26, 53].

In the CONDI-2/ERIC-PPCI trial, remote ischaemic perconditioning neither reduced infarct size (as assessed by 48-h troponin release or by CMR [n = 110]) nor improved the primary clinical endpoint (composite of cardiac mortality and heart failure hospitalisation at 12 months) [13, 18]. However, previous RIC studies have suggested the presence of discordant effects on infarct size and clinical outcomes. In the RIC-STEMI trial (n = 516), there was no reduction in infarct size with adjunctive RIC (based on 48 h troponin release) but the primary composite outcome of cardiac death and heart failure hospitalisation was significantly reduced (hazard ratio 0.35, 95% CI 0.15–0.78, median follow up 2.1 years) [14]. Other studies indicate the potential for additional cardioprotection by extending the period of conditioning beyond the time of ischaemia/reperfusion. A CMR study of postconditioning immediately after reperfusion in PPCI-treated STEMI patients (n = 122) showed no reduction in infarct size but at 1 year, adverse remodelling was reduced, especially in those with microvascular obstruction [50]. In the LIPSIA-CONDITIONING trial (n = 696), combined RIC and postconditioning resulted in greater myocardial salvage than conventional PPCI alone, and with extended follow up (median 3.6 years), a reduction in cardiac death, reinfarction and new congestive cardiac failure (10.2 versus 16.9%, p = 0.04) [8, 47]. However, in this trial, postconditioning alone did not reduce MACE (14.1 versus 16.9% in controls, p-0.41), and other postconditioning studies have also reported neutral outcomes [10, 16, 46]. Nonetheless, taken together, these results indicate that although infarct size may not be reduced with RIC, the subsequent remodelling process may be altered for therapeutic gain.

To our knowledge, ours is the only trial to evaluate CRIC post-STEMI: to date, no other clinical trial has evaluated late, repetitive RIC post-STEMI, though the CORIC-MI (n = 200) and i-RIC (n = 4700) trials will incorporate CRIC following STEMI (with additional per/postconditioning) [45, 63]. However, CRIC has been investigated in experimental animal studies. In an animal model of ischaemia/reperfusion injury, CRIC administered for 28 days resulted in improved LV remodelling and also survival (at 84 days), and, consistent with our findings, no change in infarct size [55]. Importantly, in our trial, CRIC was not commenced till day 3 post-MI. Given the critical 48 h timeframe ascribed for reperfusion injury when infarct size attenuation may be targeted therapeutically, any benefit from ‘late’ CRIC likely involves mechanisms distinct from infarct size reduction [34, 62]. Previous work has shown that cardioprotection may be mediated by dialysable humoral factors which can circulate for 6 days after a RIC stimulus [24]. Our data indicate that the benefits of CRIC are unlikely to involve haemodynamic parameters, which remained comparable in both groups at follow up (Table 1). Although microvascular obstruction, a known predictor of adverse remodelling, was more prevalent in the sham group, this did not reach statistical significance.

Nonetheless, if CRIC is beneficial, why was there no observed effect on LVEF or other volumetric indices of remodelling? Global volumetric indices integrate the function of infarcted and remote regions, and hence may be insensitive to regional dysfunction, particularly if compensatory mechanisms subsequently normalise global performance. Furthermore, gross volumetric change may only occur late in the remodelling process, in a maladaptive state beyond the point of no return. By contrast, strain imaging may prove more sensitive, identifying subtle, early and potentially reversible regional derangements in those at risk of at risk of adverse remodelling [37]. Impairment of longitudinal strain has been shown to occur early in many pathological disease states, preceding the onset of overt systolic dysfunction [7, 27].

Strain analysis may also provide pathophysiological insights into STEMI-induced remodelling. The myocardium comprises a complex spatial orientation of fibres, with subendocardial fibres orientated in a right-handed helix and subepicardial fibres, in a left-handed helix, with mid-myocardial fibres arranged circumferentially [15, 49]. This physiological arrangement is mechanically advantageous, providing energetic efficiency, with optimum redistribution of shear forces [52]. The subendocardial fibres are especially vulnerable to the effects of ischaemia, and post-MI, longitudinal function declines first [44, 54, 61]. This may be compensated by augmenting short-axis function, mediated by circumferential fibre shortening [54]. Clinical evidence suggests that whereas GLS is a better predictor of MACE (driven by ischaemic/scar-related events), GCS better predicts adverse remodelling [7, 25]. It is likely that circumferential function initially compensates for longitudinal dysfunction (and restrains ventricular dilatation), but subsequently may decline, with ensuing dilatation and adverse remodelling [48]. However, even prior to decompensation, augmented circumferential function may be maladaptive, increasing cardiac workload and shear stress in damaged regions. Myocardial stretching/thinning predisposes to the development of sphericity, which reduces mechanical advantage and is associated with adverse outcome [39, 41].

Our data show increased circumferential strain in remote as well as in infarcted segments. Studies using CMR diffusion tensor imaging have shown reorientation of fibres in remote myocardium post-MI [35, 58, 59]. Animal models show that local strain patterns may guide the alignment of collagen fibres during scar formation [12]. Hence, in the chronic phase post-STEMI, altered regional mechanics may influence the propensity to adverse remodelling. Intuitively, rather than augmenting a compensatory, potentially maladaptive mechanism, correction of the initial pathological derangement may be preferable. Our data indicate that CRIC may target the initial derangement in longitudinal function, minimising the disparity in longitudinal strain between infarcted segments and adjacent viable myocardium and lessening the requirement for circumferential compensation. This may prove mechanically and energetically advantageous and potentially mitigate against the development of heart failure [38].

Our analysis suggests that the beneficial effects of RIC may involve mechanisms distinct from infarct size limitation. This warrants further investigation in prospective studies as well as in analyses of imaging datasets acquired from previously studied RIC cohorts. Further study is required to determine whether a multi-target approach combining CRIC with ischaemic perconditioning interventions may afford a more effective, synergistic cardioprotective strategy.