Ischemic heart disease (IHD) is the leading cause of death worldwide. Novel cardioprotective strategies are therefore required to improve clinical outcomes in patients with IHD. Although a large number of novel cardioprotective strategies have been discovered in the research laboratory, their translation to the clinical setting has been largely disappointing. The reason for this failure can be attributed to a number of factors including the inadequacy of the animal ischemia-reperfusion injury models used in the preclinical cardioprotection studies and the inappropriate design and execution of the clinical cardioprotection studies. This important issue was the main topic of discussion of the UCL-Hatter Cardiovascular Institute 6th International Cardioprotection Workshop, the outcome of which has been published in this article as the "Hatter Workshop Recommendations". These have been proposed to provide guidance on the design and execution of both preclinical and clinical cardioprotection studies in order to facilitate the translation of future novel cardioprotective strategies for patient benefit.
Intercellular and inter-organ communication is required to maintain homoeostasis in multicellular organisms. Given its life-supporting function, the heart is at the centre of a heavily studied network of interactions. Despite the long-recognized ability to receive and relay inputs to and from far and close neighbours, surprising new networks of interactions as well as new communication factors and mechanisms are currently emerging. The Myocardial Function and the Cellular Biology of the Heart Working groups of the European Society of Cardiology convened during 2–5 May 2013 to discuss emerging data and ongoing studies on intercellular and inter-organ communication, in health and disease.
Cells interact through either direct contact or secreted agonists. The signal transduction machinery inside cells eventually translates interactions with limited numbers of agonists into a cellular response. This process of scanty molecules being pinpointed by high-affinity receptors is now flanked by other emerging mechanisms of communication that involve highly abundant messengers binding to relatively low-affinity detectors. Two novel intercellular communication paths are currently arising: the flooding of cells with secreted vesicles, the so-called exosomes, with various but information-rich contents, and the sensing of different species of circulating RNA, such as miRNAs that, once captured, elicit post-transcriptional regulation of gene expression, and the extracellular RNAs (eRNA) that, from the outside of cells, trigger membrane enzyme activation and generation of classical receptor agonists.
### 2.1 Exosomes and miRNA
An exciting new concept in the field of intercellular and inter-organ communication is the idea that microscopic vesicles may ferry proteins and RNA through interstitial fluid and blood. Building on this concept, miRNA and proteins from plasma microvesicles and exosomes may offer a great potential as biomarkers for cardiovascular risk and cellular injury. Specific miRNAs act as master regulators of angiogenesis, cardiomyocyte proliferation, and regulation of cell survival. In particular, the importance of miR-199, which seems to regulate a …
Time-critical acute ischemic conditions such as ST-elevation myocardial infarction and acute ischemic stroke are staples in Emergency Medicine practice. While timely reperfusion therapy is a priority, the resultant acute ischemia/reperfusion injury contributes to significant mortality and morbidity. Among therapeutics targeting ischemia/reperfusion injury (IRI), remote ischemic conditioning (RIC) has emerged as the most promising.RIC, which consists of repetitive inflation and deflation of a pneumatic cuff on a limb, was first demonstrated to have protective effect on IRI through various neural and humoral mechanisms. Its attractiveness stems from its simplicity, low-cost, safety, and efficacy, while at the same time it does not impede reperfusion treatment. There is now good evidence for RIC as an effective adjunct to reperfusion in ST-elevation myocardial infarction patients for improving clinical outcomes. For other applications such as acute ischemic stroke, subarachnoid hemorrhage, traumatic brain injury, cardiac arrest, and spinal injury, there is varying level of evidence.This review aims to describe the RIC phenomenon, briefly recount its historical development, and appraise the experimental and clinical evidence for RIC in selected emergency conditions. Finally, it describes the practical issues with RIC clinical application and research in Emergency Medicine.
Mutations in PTEN inducible kinase-1 (PINK1) induce mitochondrial dysfunction in dopaminergic neurons resulting in an inherited form of Parkinson's disease. Although PINK1 is present in the heart its exact role there is unclear. We hypothesized that PINK1 protects the heart against acute ischemia reperfusion injury (IRI) by preventing mitochondrial dysfunction.Over-expressing PINK1 in HL-1 cardiac cells reduced cell death following simulated IRI (29.2±5.2% PINK1 versus 49.0±2.4% control; N = 320 cells/group P<0.05), and delayed the onset of mitochondrial permeability transition pore (MPTP) opening (by 1.3 fold; P<0.05). Hearts excised from PINK1+/+, PINK1+/- and PINK1-/- mice were subjected to 35 minutes regional ischemia followed by 30 minutes reperfusion. Interestingly, myocardial infarct size was increased in PINK1-/- hearts compared to PINK1+/+ hearts with an intermediate infarct size in PINK1+/- hearts (25.1±2.0% PINK1+/+, 38.9±3.4% PINK1+/- versus 51.5±4.3% PINK1-/- hearts; N>5 animals/group; P<0.05). Cardiomyocytes isolated from PINK1-/- hearts had a lower resting mitochondrial membrane potential, had inhibited mitochondrial respiration, generated more oxidative stress during simulated IRI, and underwent rigor contracture more rapidly in response to an uncoupler when compared to PINK1+/+ cells suggesting mitochondrial dysfunction in hearts deficient in PINK1.We show that the loss of PINK1 increases the heart's vulnerability to ischemia-reperfusion injury. This may be due, in part, to increased mitochondrial dysfunction. These findings implicate PINK1 as a novel target for cardioprotection.
The opening of the mitochondrial permeability transition pore (mPTP) is a critical determinant of ischaemia-reperfusion injury, and preventing its opening confers powerful cardioprotection in non-diseased myocardium. Whether this cardioprotective effect is present in the setting of hypertrophic cardiomyopathy (HCM) is unknown and is investigated in this study.
Methodology
Local UCLH/UCL ethical committee approval had been granted for this study. Human adult ventricular cardiomyocytes were isolated from left ventricular septal tissue, harvested from consenting patients undergoing surgical myectomy for obstructive HCM. The cells were loaded with the fluorescent dye TMRM which localises to the mitochondria, generates oxidative stress within the mitochondria on confocal imaging, resulting in mPTP opening, as indicated by the collapse of the mitochondrial membrane potential. The time taken to induce the loss of mitochondrial membrane potential was used as a measure of mPTP opening sensitivity. Cells were randomised to the following: (1) DMSO 0.01% vehicle control (N=8/group); (2) cells pre-treated with ciclosporin-A (CsA)(0.2 μM) for 15 min (N=7/group); (3) cells pre-treated with atorvastatin (25 μM)(N=7/group).
Results
In the control group, mPTP opening was induced after 188.7%±22.7 s of oxidative stress, providing evidence for a functional mPTP in the setting of HCM. Furthermore, pretreatment with the known mPTP inhibitor, CsA, and atorvastatin, delayed the onset of mPTP opening by 51%±10% (p<0.001) and 35%±7% (p<0.05), respectively.
Conclusions
For the first time in diseased human ventricular myocytes, we have demonstrated that the mPTP is functional and that its opening can be inhibited by cardioprotective agents such as CsA and atorvastatin.
Background Whether the remote myocardium of reperfused ST ‐segment elevation myocardial infarction ( STEMI ) patients plays a part in adverse left ventricular ( LV ) remodeling remains unclear. We aimed to use automated extracellular volume fraction ( ECV ) mapping to investigate whether changes in the ECV of the remote ( ECV R emote ) and infarcted myocardium ( ECV I nfarct ) impacted LV remodeling. Methods and Results Forty‐eight of 50 prospectively recruited reperfused STEMI patients completed a cardiovascular magnetic resonance at 4±2 days and 40 had a follow‐up scan at 5±2 months. Twenty healthy volunteers served as controls. Mean segmental values for native T1, T2, and ECV were obtained. Adverse LV remodeling was defined as ≥20% increase in LV end‐diastolic volume. ECV R emote was higher on the acute scan when compared to control (27.9±2.1% vs 26.4±2.1%; P =0.01). Eight patients developed adverse LV remodeling and had higher ECV R emote acutely (29.5±1.4% vs 27.4±2.0%; P =0.01) and remained higher at follow‐up (28.6±1.5% vs 26.6±2.1%; P =0.02) compared to those without. Patients with a higher ECV R emote and a lower myocardial salvage index ( MSI ) acutely were significantly associated with adverse LV remodeling, independent of T1 Remote , T1 Core and microvascular obstruction, whereas a higher ECV I nfarct was significantly associated with worse wall motion recovery. Conclusions ECV R emote was increased acutely in reperfused STEMI patients. Those with adverse LV remodeling had higher ECV R emote acutely, and this remained higher at follow‐up than those without adverse LV remodeling. A higher ECV R emote and a lower MSI acutely were significantly associated with adverse LV remodeling whereas segments with higher ECV I nfarct were less likely to recover wall motion.
Background In severe aortic stenosis (AS), hemodynamics and conventional indices do not fully explain symptoms, prognosis or treatment response. We hypothesize that diffuse myocardial fibrosis (DMF) is a key missing factor in AS. This can now be accurately measured non-invasively using equilibrium contrast CMR (EQ-CMR) [1] involving a primed gadolinium infusion, T1 measurement preand post-infusion, and direct measure of blood volume of distribution (1-hematocrit). The derived myocardial volume of distribution (Vd(m)) correlates strongly with histological diffuse myocardial fibrosisin AS and this calibration can convert Vd(m) to DMF%. Cell volume can be calculated as 1-DMF%*LV mass.
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