Acute myocardial infarction causes lethal injury to cardiomyocytes during both ischaemia and reperfusion (IR). It is important to define the precise mechanisms by which they die in order to develop ...strategies to protect the heart from IR injury. Necrosis is known to play a major role in myocardial IR injury. There is also evidence for significant myocardial death by other pathways such as apoptosis, although this has been challenged. Mitochondria play a central role in both of these pathways of cell death, as either a causal mechanism is the case of mitochondrial permeability transition leading to necrosis, or as part of the signalling pathway in mitochondrial cytochrome c release and apoptosis. Autophagy may impact this process by removing dysfunctional proteins or even entire mitochondria through a process called mitophagy. More recently, roles for other programmed mechanisms of cell death such as necroptosis and pyroptosis have been described, and inhibitors of these pathways have been shown to be cardioprotective. In this review, we discuss both mitochondrial and mitochondrial‐independent pathways of the major modes of cell death, their role in IR injury and their potential to be targeted as part of a cardioprotective strategy. This article is part of a special Issue entitled ‘Mitochondria as targets of acute cardioprotection’ and emerged as part of the discussions of the European Union (EU)‐CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.
Cardiomyocyte cell death occurring during myocardial reperfusion (reperfusion injury) contributes to final infarct size after transient coronary occlusion. Different interrelated mechanisms of ...reperfusion injury have been identified, including alterations in cytosolic Ca2+ handling, sarcoplasmic reticulum‐mediated Ca2+ oscillations and hypercontracture, proteolysis secondary to calpain activation and mitochondrial permeability transition. All these mechanisms occur during the initial minutes of reperfusion and are inhibited by intracellular acidosis. The cGMP/PKG pathway modulates the rate of recovery of intracellular pH, but has also direct effect on Ca2+ oscillations and mitochondrial permeability transition. The cGMP/PKG pathway is depressed in cardiomyocytes by ischaemia/reperfusion and preserved by ischaemic postconditioning, which importantly contributes to postconditioning protection. The present article reviews the mechanisms and consequences of the effect of ischaemic postconditioning on the cGMP/PKG pathway, the different pharmacological strategies aimed to stimulate it during myocardial reperfusion and the evidence, limitations and promise of translation of these strategies to the clinical practice. Overall, the preclinical and clinical evidence suggests that modulation of the cGMP/PKG pathway may be a therapeutic target in the context of myocardial infarction.
Linked Articles
This article is part of a themed section on Conditioning the Heart – Pathways to Translation. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue‐8
Ageing, sex, and cardioprotection Ruiz‐Meana, Marisol; Boengler, Kerstin; Garcia‐Dorado, David ...
British journal of pharmacology,
December 2020, Volume:
177, Issue:
23
Journal Article
Peer reviewed
Open access
Translation of cardioprotective interventions aimed at reducing myocardial injury during ischaemia–reperfusion from experimental studies to clinical practice is an important yet unmet need in ...cardiovascular medicine. One particular challenge facing translation is the existence of demographic and clinical factors that influence the pathophysiology of ischaemia–reperfusion injury of the heart and the effects of treatments aimed at preventing it. Among these factors, age and sex are prominent and have a recognised role in the susceptibility and outcome of ischaemic heart disease. Remarkably, some of the most powerful cardioprotective strategies proven to be effective in young animals become ineffective during ageing. This article reviews the mechanisms and implications of the modulatory effects of ageing and sex on myocardial ischaemia–reperfusion injury and their potential effects on cardioprotective interventions.
LINKED ARTICLES
This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc
After a reperfused myocardial infarction (MI), dynamic tissue changes occur (edema, inflammation, microvascular obstruction, hemorrhage, cardiomyocyte necrosis, and ultimately replacement by ...fibrosis). The extension and magnitude of these changes contribute to long-term prognosis after MI. Cardiac magnetic resonance (CMR) is the gold-standard technique for noninvasive myocardial tissue characterization. CMR is also the preferred methodology for the identification of potential benefits associated with new cardioprotective strategies both in experimental and clinical trials. However, there is a wide heterogeneity in CMR methodologies used in experimental and clinical trials, including time of post-MI scan, acquisition protocols, and, more importantly, selection of endpoints. There is a need for standardization of these methodologies to improve the translation into a real clinical benefit. The main objective of this scientific expert panel consensus document is to provide recommendations for CMR endpoint selection in experimental and clinical trials based on pathophysiology and its association with hard outcomes.
New findings
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What is the central question of this study?
Ischaemia–reperfusion of peripheral tissues protects the heart from subsequent myocardial ischaemia–reperfusion‐induced injury and cardiac ...dysfunction, a phenomenon referred to as ‘remote ischaemic preconditioning’ (rIPC). This study addressed whether activation of sensory afferent nerves in the ischaemic hindlimb and vagal efferent nerves innervating the heart mediate rIPC.
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What is the main finding and its importance?
Spinal cord section, bilateral vagotomy or blockade of muscarinic cholinergic receptors in vivo abolished rIPC and cardioprotection measured in vitro. Electrical stimulation of the vagus nerve induced cardioprotection, thus mimicking rIPC. The finding that sensory and parasympathetic neural mechanisms mediate rIPC confirms and extends previous results, with implications for translational studies in patients with coronary artery disease.
This investigation was designed to determine the participation of the vagus nerve and muscarinic receptors in the remote ischaemic preconditioning (rIPC) mechanism. New Zealand rabbits were anaesthetized, and the femoral artery was dissected. After 30 min of monitoring, the hearts were isolated and subjected to 30 min of global no‐flow ischaemia and 180 min of reperfusion (non‐rIPC group). The ventricular function was evaluated, considering the left ventricular developed pressure and the left ventricular end‐diastolic pressure. In the rIPC group, the rabbits were subjected to three cycles of hindlimb ischaemia (5 min) and reperfusion (5 min), and the same protocol as that used in non‐rIPC group was then repeated. In order to evaluate the afferent neural pathway during the rIPC protocol we used two groups, one in which the femoral and sciatic nerves were sectioned and the other in which the spinal cord was sectioned (T9–T10 level). To study the efferent neural pathway during the rIPC protocol, the vagus nerve was sectioned and, in another group, atropine was administered. The effect of vagal stimulation was also evaluated. An infarct size of 40.8 ± 3.1% was obtained in the non‐rIPC group, whereas in rIPC group the infarct size decreased to 16.4 ± 3.5% (P < 0.05). During the preconditioning protocol, the vagus nerve section and the atropine administration each abolished the effect of rIPC on infarct size. Vagal stimulation mimicked the effect of rIPC, decreasing infarct size to 15.2 ± 4.7% (P < 0.05). Decreases in infarct size were accompanied by improved left ventricular function. We demonstrated the presence of a neural afferent pathway, because the spinal cord section completely abolished the effect of rIPC on infarct size. In conclusion, rIPC activates a neural afferent pathway, the cardioprotective signal reaches the heart through the vagus nerve (efferent pathway), and acetylcholine activates the ischaemic preconditioning phenomenon when acting on the muscarinic receptors.
In patients with bicuspid valve (BAV), ascending aorta (AAo) dilatation may be caused by altered flow patterns and wall shear stress (WSS). These differences may explain different aortic dilatation ...morphotypes. Using 4D-flow cardiovascular magnetic resonance (CMR), we aimed to analyze differences in flow patterns and regional axial and circumferential WSS maps between BAV phenotypes and their correlation with ascending aorta dilatation morphotype.
One hundred and one BAV patients (aortic diameter ≤ 45 mm, no severe valvular disease) and 20 healthy subjects were studied by 4D-flow CMR. Peak velocity, flow jet angle, flow displacement, in-plane rotational flow (IRF) and systolic flow reversal ratio (SFRR) were assessed at different levels of the AAo. Peak-systolic axial and circumferential regional WSS maps were also estimated. Unadjusted and multivariable adjusted linear regression analyses were used to identify independent correlates of aortic root or ascending dilatation. Age, sex, valve morphotype, body surface area, flow derived variables and WSS components were included in the multivariable models.
The AAo was non-dilated in 24 BAV patients and dilated in 77 (root morphotype in 11 and ascending in 66). BAV phenotype was right-left (RL-) in 78 patients and right-non-coronary (RN-) in 23. Both BAV phenotypes presented different outflow jet direction and velocity profiles that matched the location of maximum systolic axial WSS. RL-BAV velocity profiles and maximum axial WSS were homogeneously distributed right-anteriorly, however, RN-BAV showed higher variable profiles with a main proximal-posterior distribution shifting anteriorly at mid-distal AAo. Compared to controls, BAV patients presented similar WSS magnitude at proximal, mid and distal AAo (p = 0.764, 0.516 and 0.053, respectively) but lower axial and higher circumferential WSS components (p < 0.001 for both, at all aortic levels). Among BAV patients, RN-BAV presented higher IRF at all levels (p = 0.024 proximal, 0.046 mid and 0.002 distal AAo) and higher circumferential WSS at mid and distal AAo (p = 0.038 and 0.046, respectively) than RL-BAV. However, axial WSS was higher in RL-BAV compared to RN-BAV at proximal and mid AAo (p = 0.046, 0.019, respectively). Displacement and axial WSS were independently associated with the root-morphotype, and circumferential WSS and SFRR with the ascending-morphotype.
Different BAV-phenotypes present different flow patterns with an anterior distribution in RL-BAV, whereas, RN-BAV patients present a predominant posterior outflow jet at the sinotubular junction that shifts to anterior or right anterior in mid and distal AAo. Thus, RL-BAV patients present a higher axial WSS at the aortic root while RN-BAV present a higher circumferential WSS in mid and distal AAo. These results may explain different AAo dilatation morphotypes in the BAV population.
Protection by ischemic preconditioning is lost in cardiomyocytes and hearts of heterozygous connexin 43 deficient (Cx43+/-) mice. Because connexin 43 (Cx43) is localized in cardiomyocyte mitochondria ...and mitochondrial Cx43 content is increased with ischemic preconditioning, we now tried to identify a functional defect at the level of the mitochondria in Cx43+/- mice by use of diazoxide and menadione. Diazoxide stimulates the mitochondrial formation of reactive oxygen species (ROS) and menadione generates superoxide at multiple intracellular sites; both substances elicit cardioprotection through increased ROS formation. ROS formation in response to the potassium ionophore valinomycin was also measured for comparison. Menadione (2 micromol/L) and valinomycin (10 nmol/L) induced similar ROS formation in wild-type (WT) and Cx43+/- cardiomyocytes. In contrast, diazoxide (200 micromol/L) increased ROS formation by 43+/-10% versus vehicle in WT, but only by 18+/-4% in Cx43+/- cardiomyoctes (P<0.05). Two hour-simulated ischemia and oxygenated, hypo-osmolar reperfusion reduced viability as compared with normoxia (WT: 7+/-1% versus 39+/-2%, (Cx43+/-): 8+/-1% versus 40+/-3%, P<0.01). Although menadione protected WT and Cx43+/- cardiomyocytes, diazoxide increased viability (17+/-2%, P<0.01) in WT, but not in Cx43+/- (9+/-1%). Menadione (37 microg/kg i.v.) before 30 minutes coronary occlusion and 2 hour reperfusion reduced infarct size in WT and Cx43+/- mice (24+/-4% versus 24+/-5%). In contrast, diazoxide (5 mg/kg i.v.) reduced infarct size in WT (35+/-4% versus 55+/-3% of area at risk, P<0.01), but not in Cx43+/- mice (56+/-2% versus 54+/-3%). Cardiomyocytes of Cx43+/- mice have a specific functional deficit in ROS formation in response to diazoxide and accordingly less protection.
Objective Management and follow-up of chronic aortic dissections continue to be a clinical challenge due to progressive dilatation and subsequent rupture. To predict complications, guidelines suggest ...follow-up of aortic diameter. However, dilatation is triggered by hemodynamic parameters (pressures/wall shear stresses) and geometry of false (FL) and true lumen (TL), information not captured by diameter alone. Therefore, we aimed at better understanding the influence of dissection anatomy on TL and FL hemodynamics. Methods In vitro studies were performed using pulsatile flow in realistic dissected latex/silicone geometries with varying tear number, size, and location. We assessed three different conformations: (1) proximal tear only; (2) distal tear only; (3) both proximal and distal tears. All possible combinations (n = 8) of small (10% of aortic diameter) and large (25% of aortic diameter) tears were considered. Pressure, velocity, and flow patterns were analyzed within the lumina (at proximal and distal sections) and at the tears. We also computed the FL mean pressure index (FPImean %) as a percentage of the TL mean pressure, to compare pressures among models. Results The presence of large tears equalized FL/TL pressures compared with models with only small tears (proximal FPImean % 99.85 ± 0.45 vs 92.73 ± 3.63; distal FPImean % 99.51 ± 0.80 vs 96.35 ± 1.96; P < .001). Thus, large tears resulted in slower velocities through the tears (systolic velocity <180 cm/s) and complex flows within the FL, whereas small tears resulted in lower FL pressures, higher tear velocities (systolic velocity >290 cm/s), and a well-defined flow. Additionally, both proximal and distal tears act as entry and exit. During systole, flow enters the FL through all tears simultaneously, while during diastole, flow leaves through all communications. Flow through the FL, from proximal to distal tears or vice versa, is minimal. Conclusions Our results suggest that FL hemodynamics heavily depends on cumulative tear size, and thus, it is an important parameter to take into account when clinically assessing chronic aortic dissections.
This study sought to establish the best definition of left ventricular adverse remodeling (LVAR) to predict outcomes and determine whether its assessment adds prognostic information to that obtained ...by early cardiac magnetic resonance (CMR).
LVAR, usually defined as an increase in left ventricular end-diastolic volume (LVEDV) is the main cause of heart failure after an ST-segment elevated myocardial infarction; however, the role of assessment of LVAR in predicting cardiovascular events remains controversial.
Patients with ST-segment elevated myocardial infarction who received percutaneous coronary intervention within 6 h of symptom onset were included (n = 498). CMR was performed during hospitalization (6.2 ± 2.6 days) and after 6 months (6.1 ± 1.8 months). The optimal threshold values of the LVEDV increase and the LV ejection fraction decrease associated with the primary endpoint were ascertained. Primary outcome was a composite of cardiovascular mortality, hospitalization for heart failure, or ventricular arrhythmia.
The study was completed by 374 patients. Forty-nine patients presented the primary endpoint during follow-up (72.9 ± 42.8 months). Values that maximized the ability to identify patients with and without outcomes were a relative rise in LVEDV of 15% (hazard ratio HR: 2.1; p = 0.007) and a relative fall in LV ejection fraction of 3% (HR: 2.5; p = 0.001). However, the predictive model (using C-statistic analysis) failed to demonstrate that direct observation of LVAR at 6 months adds information to data from early CMR in predicting outcomes (C-statistic: 0.723 vs. 0.795).
The definition of LVAR that best predicts adverse cardiovascular events should consider both the increase in LVEDV and the reduction in LV ejection fraction. However, assessment of LVAR does not improve information provided by the early CMR.
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