Comment

Postconditioning for protection of the infarcting heart

The phospholipid bilayer membrane that surrounds each cell in the body represents the first and last line of defense for preserving overall cell viability. In several forms of cardiac and skeletal muscle disease, deficits in the integrity of the muscle membrane play a central role in disease pathogenesis. In Duchenne muscular dystrophy, an inherited and uniformly fatal disease of progressive muscle deterioration, muscle membrane instability is the primary cause of disease, including significant heart disease, for which there is no cure or highly effective treatment. Further, in multiple clinical forms of myocardial ischemia-reperfusion injury, the cardiac sarcolemma is damaged and this plays a key role in disease etiology. In this review, cardiac muscle membrane stability is addressed, with a focus on synthetic block copolymers as a unique chemical-based approach to stabilize damaged muscle membranes. Recent advances using clinically relevant small and large animal models of heart disease are discussed. In addition, mechanistic insights into the copolymer-muscle membrane interface, featuring atomistic, molecular, and physiological structure-function approaches are highlighted. Collectively, muscle membrane instability contributes significantly to morbidity and mortality in prominent acquired and inherited heart diseases. In this context, chemical-based muscle membrane stabilizers provide a novel therapeutic approach for a myriad of heart diseases wherein the integrity of the cardiac muscle membrane is at risk.

Both morphine and limb remote ischemic perconditioning (RIPer) can protect against myocardial ischemia/reperfusion injury (IRI). This experiment was designed to assess whether combined morphine and limb RIPer could provide and enhanced protection against myocardial IRI in an in vivo rat model.

One hundred male Sprague–Dawley rats were randomly allocated to six groups: sham, ischemia/reperfusion (IR), ischemic preconditioning, RIPer, morphine (M), and combined morphine and remote ischemic perconditioning (M + RIPer). Ventricular arrhythmias that occurred during ischemia and early reperfusion were scored, and serum creatine kinase isoenzyme and cardiac troponin I levels were assayed. The infarct size was determined by Evans blue and triphenyl tetrazolium chloride staining. The apoptosis in the myocardial ischemic core, ischemic border, and nonischemic areas was assessed through real-time polymerase chain reaction for Bax and Bcl-2 and with the transferase-mediated deoxyuridine triphosphate-biotin nick end labeling assay.

The infarct size, serum cardiac troponin I level, incidence, and score of the arrhythmias during the initial reperfusion were significantly reduced in the M + RIPer group compared with the IR group but did not differ significantly between the ischemic preconditioning and M + RIPer groups. Transferase-mediated deoxyuridine triphosphate-biotin nick end labeling–positive cells were significantly decreased, and the Bcl-2/Bax ratio was significantly increased in the M + RIPer group compared with the IR group.

This experiment demonstrates that combined morphine and limb RIPer provides an enhanced protection against myocardial IRI by the Bcl-2-linked apoptotic signaling pathway.

This study investigated the effects of aortic root infusion of sufentanil on myocardial ischemia/reperfusion injury in patients undergoing elective mitral valve replacement (MVR) with cardiopulmonary bypass (CPB).

A prospective, randomized, clinical study.

A university-affiliated teaching hospital.

Fifty-three adult patients undergoing elective MVR with CPB.

Bolus infusions of sufentanil (0.2 μg/kg, n = 24) or normal saline (n = 29) were administered through the aortic root cardioplegia perfusion catheter 5 minutes before aortic unclamping.

Plasma concentrations of CK-MB and cTnI and variables including heart rate, mean arterial pressure, central venous pressure, cardiac output, stroke volume, duration of mechanical ventilation, length of ICU stay, length of hospital stay, and 24-hour postoperative inotropic scores were recorded. Plasma concentrations of CK-MB and cTnI were significantly lower 4 and 8 hours after aortic unclamping in the sufentanil postconditioning group compared to control (p<0.05). Inotropic drug use, duration of mechanical ventilation, and length of ICU and hospital stays were reduced significantly in the sufentanil postconditioning group compared to control (p< 0.05).

The present study demonstrated that sufentanil can attenuate myocardial ischemia-reperfusion injury in patients undergoing elective MVR with CPB.

This study was designed to assess the neuroprotective effect of xenon-induced delayed postconditioning on spinal cord ischaemia–reperfusion injury (IRI) and to determine the time of administration for best neuroprotection in a rat model of spinal cord IRI.

Fifty male rats were randomly divided equally into a sham group, control group, and three xenon postconditioning groups (n=10 per group). The control group underwent spinal cord IRI and immediately inhaled 50% nitrogen/50% oxygen for 3 h at the initiation of reperfusion. The three xenon postconditioning groups underwent the same surgical procedure and immediately inhaled 50% xenon/50% oxygen for 3 h at the initiation of reperfusion or 1 and 2 h after reperfusion. The sham operation group underwent the same surgical procedure without aortic occlusion, and inhaled 50% nitrogen/50% oxygen. Neurological function was assessed using the Basso, Beattie, and Bresnahan score at 4, 24, and 48 h of reperfusion. Histological examination was performed using Nissl staining and immunohistochemistry, and apoptosis was detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labelling staining.

Compared with the control group, the three xenon postconditioning groups showed improvements in neurological outcomes, and had more morphologically normal neurones at 48 h of reperfusion. Apoptotic cell death was reduced and the ratio of Bcl-2/Bax immunoreactivity increased in xenon-treated rats compared with controls.

Xenon postconditioning up to 2 h after reperfusion provided protection against spinal cord IRI in rats, but the greatest neuroprotection occurred with administration of xenon for 1 h at reperfusion.

The physiological and pathological roles of dopamine D2 receptors (DR2) in the regulation of cardiovacular functions have been recognized. DR2 activation protects hypoxia/reoxygenation (H/R)-induced cardiomyocyte injury and apoptosis, and ischemic post-conditioning (PC) plays a critical role in cardioprotection as well; however the involvement of the DR2 activation in the PC-induced cardioprotection is unknown. In the present study, we found that the H/R increased the expressions of DR2 mRNA and protein in cardiomyocytes, which were significantly enhanced by PC. Bromocriptine (Bro, a DR2 agonist) further increased DR2 expression, but Haloperidol (Hal, a DR2 antagonist) reversed the Bro-induced DR2 expressions. PC protected against H/R-induced apoptosis, the rise of [Ca²⁺]_i, the expressions of cleaved caspase-3 and -9, release of cytochrome c, and mPTP opening. In addition, PC counteracted the reduction of cell viability caused by H/R, increased the phosphorylation of ERK1/2, PI3K, Akt, GSK-3β and mitochondrial membrane potential. PC further increased Bcl-2 expression, promoted PKC-ε translocation to cell membrane, and activated the mitochondrial ATP-sensitive K channels (mK_ATP). Bro further enhanced the cardioprotective roles of PC, but Hal reversed these effects of Bro. Meanwhile, we found that DR2 was expressed in cell membrane and interacted with PKC-ε in PC. In conclusion, these results suggest that PC attenuates cardiomyocyte apoptosis via inhibition of mPTP opening by DR2-mediated activation of ERK1/2, PI3K–Akt–GSK-3β and PKC-ε–mK_ATP. These findings provide a novel target for the treatment of ischemic cardiomyopathy.

To assess the association between smoking and survival with a good neurologic outcome in patients following cardiac arrest treated with mild therapeutic hypothermia (TH).

We conducted a retrospective observational study of a prospectively collected cohort of 188 consecutive patients following cardiac arrest treated with TH between May 2007 and January 2012. Smoking status was retrospectively collected via chart review and was classified as “ever” or “never”. Primary endpoint was survival to hospital discharge with a good neurologic outcome and was compared between smokers and nonsmokers. Logistic regression analysis was used to assess the association between smoking status and neurologic outcome at hospital discharge; adjusting for age, initial rhythm, time to return of spontaneous circulation (ROSC), bystander CPR, and time to initiation of TH.

Smokers were significantly more likely to survive to hospital discharge with good neurologic outcome compared to nonsmokers (50% vs. 28%, p = 0.003). After adjusting for age, initial rhythm, time to ROSC, bystander CPR, and time to initiation of TH, a history of smoking was associated with increased odds of survival to hospital discharge with good neurologic outcome (OR 3.54, 95% CI 1.41–8.84, p = 0.007).

Smoking is associated with improved survival with good neurologic outcome in patients following cardiac arrest. We hypothesize that our findings reflect global ischemic conditioning caused by smoking.