Int J Cardiol. 2016 Oct 1;220:146-8.

Impact of postconditioning with lactate-enriched blood on in-hospital outcomes of patients with ST-segment elevation myocardial infarction.

Koyama T1, Munakata M2, Akima T2, Kageyama T3, Shibata M3, Moritani K3, Kanki H2, Ishikawa S2, Mitamura H3.
  • 1Cardiology Department, Saitama Municipal Hospital, 2460 Mimuro, Midori-ku, Saitama City, Saitama 336-8522, Japan. Electronic address: koyamas@me.com.
  • 2Cardiology Department, Saitama Municipal Hospital, 2460 Mimuro, Midori-ku, Saitama City, Saitama 336-8522, Japan.
  • 3Cardiovascular Center, Tachikawa Hospital, 4-2-22 Nishiki, Tachikawa, Tokyo 190-8531, Japan.

Abstract

BACKGROUND:

Reperfusion injury offsets the beneficial effects of reperfusion therapy for ST-segment elevation myocardial infarction (STEMI). In our previous reports, postconditioning with lactate-enriched blood (PCLeB) induced excellent microcirculation recovery and less inflammation in STEMI patients. This study aimed to determine the in-hospital outcomes of STEMI patients treated using PCLeB.

METHODS:

Fifty-five consecutive STEMI patients were treated using PCLeB (Age 66.6±13.8years, 76.4% men) within 12h of symptom onset. In our modified postconditioning protocol, the duration of each brief reperfusion was prolonged from 10s to 60s in a stepwise manner. Lactated Ringer’s solution (20-30mL) was injected directly into the culprit coronary artery at the end of each brief reperfusion and the balloon was quickly inflated at the lesion site, whereby lactate could be trapped inside the ischemic myocardium. Each brief ischemic period lasted 60s. After 7cycles of balloon inflation and deflation, full reperfusion was performed. Thereafter, stenting was performed and percutaneous coronary intervention (PCI) was completed.

RESULTS:

The mean corrected thrombolysis in myocardial infarction frame count was 20.1±10.1 after PCI completion. The mean peak serum creatine kinase and creatine kinase-MB levels were 2751±2227IU/L and 276±181IU/L respectively. None of the study patients died during their hospital stay or required continuation of oral diuretic or inotropic therapy for heart failure on discharge.

CONCLUSIONS:

PCLeB led to zero in-hospital mortality and no overt heart failure on discharge in 55 consecutive STEMI patients undergoing reperfusion therapy.

KEYWORDS: C-reactive protein; Cardioprotection; Heart failure; Mortality; Reperfusion injury; TIMI frame count

PMID: 27379916; DOI:10.1016/j.ijcard.2016.06.176

 

Supplement:

Timely restoration of coronary blood flow is crucial for salvaging myocardial cells from ischemic cell death. However, reperfusion injury offsets the beneficial effects of reperfusion therapy for ST-segment elevation myocardial infarction (STEMI), thus limiting the myocardial salvaging effects of reperfusion therapy. Consequently, the reduction in acute mortality in patients with STEMI treated with the current reperfusion therapy has translated into a resultant increase in morbidity of post-infarction chronic heart failure.

Thus far, no approach has proven successful in preventing reperfusion injury in the clinical setting. Currently, the most popular mechanism responsible for reperfusion injury is mitochondrial permeability transition (MPT), which starts within minutes of reperfusion of ischemic myocardium and leads to uncoupling of oxidative phosphorylation, resulting in ATP depletion [1]. However, in a recent large-scale clinical trial, cyclosporine, a potent inhibitor of MPT, failed to improve the long-term outcomes of patients with STEMI and failed to prevent left ventricular remodeling, causing confusion in the field of both clinical and basic research on myocardial reperfusion injury [2].

Meanwhile, we recently reported a new approach for preventing reperfusion injury in patients with STEMI, which we named “postconditioning with lactate-enriched blood (PCLeB)” [3,4]. This approach specifically targets hypercontracture development induced by reperfusion, instead of MPT. Reperfusion-induced hypercontracture is a phenomenon resulting from the formation of rigor bonds between actin and myosin. The strong mechanical force generated by hypercontracture not only induces contraction band necrosis but also causes microvascular obstruction by compressing the microvasculature from outside the vessel walls. While no study has determined the causal relationship between MPT and hypercontracture development, a well-developed hypercontracture (contraction band necrosis) is reportedly observed within 120 s of reperfusion of ischemic myocardium in animal experiments [5]. Therefore, the development of a mature hypercontracture appears to coincide chronologically with the onset of MPT because opening of the MPT pore reportedly occurs within minutes of reperfusion [1]. Although MPT may play an important role in the development of reperfusion injury, its role in hypercontracture development is rather doubtful. We therefore postulated that hypercontracture was the primary cause of reperfusion injury and attempted to prevent hypercontracture development for the prevention of reperfusion injury in patients with STEMI.

PCLeB is a modified postconditioning protocol that consists of intermittent reperfusion and timely coronary injections of lactated Ringer’s solution, aiming to achieve controlled reperfusion with cellular oxygenation and minimal lactate washout from the cells. An ischemic myocardium ceases contraction to save ATP by accumulating lactate. Delayed lactate washout may therefore be expected to attenuate rapid contractile force recovery immediately after reperfusion and possibly prevent hypercontracture. In other words, we employed lactate as an inherent contractile activity blocker to prevent the rapid recovery of contractile force immediately after reperfusion, which otherwise might result in hypercontracture development. In our protocol, the duration of each brief reperfusion is prolonged from 10 s to 60 s in a stepwise manner. Lactated Ringer’s solution (20–30 mL) containing 28 mM lactate is injected directly in the culprit coronary artery at the end of each brief reperfusion, and the balloon is quickly inflated at the site of the lesion to trap the lactate inside the ischemic myocardium. Each brief ischemic period lasts 60 s. After 7 cycles of balloon inflation and deflation, full reperfusion is performed. Stenting is performed thereafter, and percutaneous coronary intervention (PCI) is completed.

We have repeatedly reported augmented microcirculation recovery in STEMI patients treated with PCLeB [3,4,6]. The coronary angiography (CAG) findings of a representative patient are shown in Fig. 1. The myocardium was well stained by the contrast medium, followed by prompt drainage of the contrast medium to the venous system. Currently, we have treated 66 consecutive STEMI patients by using PCLeB. The mean corrected thrombolysis in myocardial infarction (TIMI) frame count for all the 66 patients (19.6 ± 9.6 frames) was smaller than the normal value (21 frames). The augmented microcirculation recovery, consistently achieved by using PCLeB, may indicate successful attenuation of the strong compressive force generated by hypercontracture, thus avoiding microvascular obstruction. This may assure that our approach works.

Quite recently, we reported the absence of reperfusion-induced arrhythmia in 58 consecutive patients with STEMI treated with PCLeB [7]. None of the patients experienced ventricular tachycardia or fibrillation during reperfusion. This may indicate that the additional insult to the ischemic myocardium upon reperfusion was minimal, leading to the expectation for improved outcomes of these patients.

In this index paper published in the Int J Cardiol 2016;220:146-148, we reported excellent in-hospital outcomes of STEMI patients treated with PCLeB. PCLeB led to zero in-hospital mortality and no overt heart failure on discharge in 55 consecutive STEMI patients. None of the patients required continued oral diuretic or inotropic therapy on discharge, not even those with pulmonary congestion and those who required temporary use of a diuretic during the early admission period. Given these results, PCLeB seems to have definite cardioprotective effects and may be a promising approach for preventing reperfusion injury in STEMI patients undergoing reperfusion therapy.

 

Figure 1. Coronary angiography findings of a representative patient (a 74-year-old man), obtained before and after percutaneous coronary intervention (PCI). A) An angiogram obtained before PCI, showing total occlusion of the proximal right coronary artery. B) Final view of the angiogram after stenting. Marked staining of the myocardium with contrast medium can be observed (surrounded by white arrows). C) Late phase of the final view of the angiogram. Vigorous venous drainage can be observed (black arrows).

 

References

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  7. Akima T, Koyama T, Munakata M, et al. Absence of reperfusion-induced arrhythmia in patients with ST-segment elevation myocardial infarction treated using postconditioning with lactate-enriched blood. Int J Cardiol 2016;222:780-781.

 

 

 

 

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