Repeated remote ischemic conditioning attenuates left ventricular remodeling via exosome-mediated intercellular communication on chronic heart failure after myocardial infarction
Introduction
Chronic heart failure (CHF) is a clinical syndrome representing the end-stage of a number of different cardiac diseases. It causes exercise intolerance, impairs quality of life, and has been associated with high morbidity and mortality. Although the existing pharmacological therapies, such as inhibitors of the renin–angiotensin–aldosterone system and β-adrenoreceptor blockers improved outcomes in CHF [1], [2], [3], [4], they are still not optimal and cannot fully prevent progressive cardiac remodeling and dysfunction. Recently, several non-pharmacological therapies such as cardiac rehabilitation and ventilatory support have been developed [5], [6]. However, these therapies are associated with tolerability issues, and not all CHF patients benefit from them. Therefore, there is a need to develop a novel therapy that is easy to perform and is well tolerated.
The cardioprotective effect of remote ischemic preconditioning was originally reported by Przykelenk et al. [7]. They reported that ischemic preconditioning in the left circumflex coronary artery attenuated ischemia-reperfusion (IR) injury by subsequent occlusion of the left anterior descending coronary artery (LAD). Thereafter, some reports have shown that ischemic preconditioning [8], [9] and postconditioning [10], [11] of the extremities can protect the heart from IR injury. Thus, remote ischemic conditioning (RIC) may be one of the therapeutic strategies for protecting organs or tissue against IR injury. Briefly repeated non-lethal ischemia and reperfusion of a remote organ or tissue increase heart tolerability to acute IR injury. Although various studies supported the beneficial effect of RIC against acute myocardial infarction (MI), it is still unclear whether RIC is beneficial for CHF.
In this study, we hypothesized that the efficacy of RIC can expand not only to IR injury in the acute phase of MI but to left ventricular (LV) dysfunction in the chronic phase of MI. Our results showed that RIC treatment improved LV dysfunction and attenuated LV interstitial fibrosis in an experimental CHF model. These results may have clinical implications for the treatment of patients with evolving LV dysfunction.
Section snippets
Animals and experimental design
All procedures were performed in accordance to Osaka City University animal care guidelines, which conform to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996). The 8-week-old male Wistar rats weighing 260–290 g were purchased from CLEA Japan, Inc (Osaka, Japan).
The rats were intubated and were under mechanical ventilation with adequate anesthesia by pentobarbital (50 mg·kg− 1, intraperitoneally). Then,
Effects of RIC treatment on hemodynamic status and body weight
Laser Doppler blood flow measurement was performed to confirm successful transient hindlimb ischemia by RIC treatment (Fig. 1B). During RIC treatment, blood flow in the hindlimb was diminished. Since the tourniquet was released, blood flow was recovered; moreover increased. Despite the increase of peripheral blood flow after RIC treatment, there was no significant difference in hemodynamic status such as BP and HR among the groups (Fig. 1C). Thus, RIC does not affect hemodynamic status.
Discussion
Ischemic conditioning is well known as a novel strategy of protecting IR injury in coronary heart diseases, and is attracting extensive interest of clinical cardiologists. Cardiomyocytes acquire tolerability against IR injury not only by ischemic conditioning of itself, but also by ischemic conditioning of remote organs. Recent studies indicate that RIC treatment reduces the infarct size due to MI [23]. We focused on the possibility of therapeutic effect of RIC against CHF and demonstrated the
Funding sources
This study was supported in part by Grant-in-Aid for Scientific Research (24591101, 26460344 and 26461081) from the Ministry of Education, Culture, Sports, Science, and Technology, and Hoansha Foundation.
Conflicts of interest
The authors have no conflicts to report.
Acknowledgments
The authors would like to thank Ms. Chiori Asahi for her technical assistance.
References (35)
- et al.
A hard look at angiotensin receptor blockers in heart failure
J. Am. Coll. Cardiol.
(2004) - et al.
Effects of exercise training in patients with congestive heart failure: a critical review
J. Am. Coll. Cardiol.
(1995) - et al.
Adaptive servoventilation for treatment of sleep-disordered breathing in heart failure: a systematic review and meta-analysis
Chest
(2012) - et al.
Remote ischemic preconditioning: a novel protective method from ischemia reperfusion injury—a review
J. Surg. Res.
(2008) - et al.
Lipid synthesis is promoted by hypoxic adipocyte-derived exosomes in 3 T3-L1 cells
Biochem. Biophys. Res. Commun.
(2014) - et al.
Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial
Lancet
(2010) - et al.
Exosomes: extracellular organelles important in intercellular communication
J. Proteomics
(2010) - et al.
New insights into IGF-1 signaling in the heart
Trends Endocrinol. Metab.
(2014) - et al.
Insulin-like growth factor-I and angiographically documented coronary artery disease
Am. J. Cardiol.
(1996) - et al.
Enhanced mesenchymal cell engraftment by IGF-1 improves left ventricular function in rats undergoing myocardial infarction
Int. J. Cardiol.
(2010)
Renin–angiotensin–aldosterone system blockade for cardiovascular diseases: current status
Br. J. Pharmacol.
Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study
Circulation
Eplerenone in patients with systolic heart failure and mild symptoms
N. Engl. J. Med.
Regional ischemic preconditioning protects remote virgin myocardium from subsequent sustained coronary-occlusion
Circulation
Expression of heat shock protein after ischemic preconditioning in rabbit hearts
Jpn. Circ. J.
Remote postconditioning — brief renal ischemia and reperfusion applied before coronary artery reperfusion reduces myocardial infarct size via endogenous activation of adenosine receptors
Basic Res. Cardiol.
Repeated remote ischemic postconditioning protects against adverse left ventricular remodeling and improves survival in a rat model of myocardial infarction
Circ. Res.
Cited by (143)
Cardiosome-mediated protection in myocardial ischemia
2023, Clinica Chimica ActaTransient cardioprotective effects of remote ischemic postconditioning on non-reperfused myocardial infarction: longitudinal evaluation study in pigs
2022, International Journal of CardiologyCitation Excerpt :Interestingly, RIPostC animals in our current study presented less-enlarged cardiac volume (EDV) at the subacute phase in association with non-statistically reduced MMP-2 levels. Yamaguchi et al. [25] reported that repeated RIPostC could attenuate LV remodeling at the chronic phase by reducing myocardial interstitial fibrosis in HF rats. However, in the current study, no pronounced effects on adverse remodeling were observed during chronic phases.
Anti-angiogenic effect of exo-LncRNA TUG1 in myocardial infarction and modulation by remote ischemic conditioning
2023, Basic Research in Cardiology