Novel targets and future strategies for acute cardioprotection: Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart.

Ischaemic heart disease and the heart failure that often results, remain the leading causes of death and disability in Europe and worldwide. As such, in order to prevent heart failure and improve clinical outcomes in patients presenting with an acute ST-segment elevation myocardial infarction and patients undergoing coronary artery bypass graft surgery, novel therapies are required to protect the heart against the detrimental effects of acute ischaemia/reperfusion injury (IRI). During the last three decades, a wide variety of ischaemic conditioning strategies and pharmacological treatments have been tested in the clinic-however, their translation from experimental to clinical studies for improving patient outcomes has been both challenging and disappointing. Therefore, in this Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart, we critically analyse the current state of ischaemic conditioning in both the experimental and clinical settings, provide recommendations for improving its translation into the clinical setting, and highlight novel therapeutic targets and new treatment strategies for reducing acute myocardial IRI.

Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery.

To commemorate the auspicious occasion of the 30th anniversary of IPC, leading pioneers in the field of cardioprotection gathered in Barcelona in May 2016 to review and discuss the history of IPC, its evolution to IPost and RIC, myocardial reperfusion injury as a therapeutic target, and future targets and strategies for cardioprotection. This article provides an overview of the major topics discussed at this special meeting and underscores the huge importance and impact, the discovery of IPC has made in the field of cardiovascular research.

Pre-clinical Experience with a Multi-Chordal Patch for Mitral Valve Repair.

Surgical repair of flail mitral valve leaflets with neochordoplasty has good outcomes, but implementing it in anterior and bi-leaflet leaflet repair is challenging. Placing and sizing individual neochordae is time consuming and error prone, with persistent localized flail if performed incorrectly. In this study, we report our pre-clinical experience with a novel multi-chordal patch for mitral valve repair. The device was designed based on human cadaver hearts, and laser cut from expanded polytetrafluoroethylene. The prototypes were tested in: (stage 1) ex vivo hearts with leaflet flail (N = 6), (stage 2) acute swine induced with flail (N = 6), and (stage 3) two chronic swine survived to 23 and 120 days (N = 2). A2 and P2 prolapse were successfully repaired with coaptation length restored to 8.1 ± 2.2mm after posterior repair and to 10.2 ± 1.3mm after anterior repair in ex vivo hearts. In vivo, trace regurgitation was seen after repair with excellent patch durability, healing, and endothelialization at euthanasia. A new device for easier mitral repair is reported, with good early pre-clinical outcomes.

Adenosine, lidocaine and Mg2+ improves cardiac and pulmonary function, induces reversible hypotension and exerts anti-inflammatory effects in an endotoxemic porcine model.

INTRODUCTION: The combination of Adenosine (A), lidocaine (L) and Mg(2+) (M) (ALM) has demonstrated cardioprotective and resuscitative properties in models of cardiac arrest and hemorrhagic shock. This study evaluates whether ALM also demonstrates organ protective properties in an endotoxemic porcine model. METHODS: Pigs (37 to 42 kg) were randomized into: 1) Control (n = 8) or 2) ALM (n = 8) followed by lipopolysaccharide infusion (1 µg ∙ kg(-1) ∙ h(-1)) for five hours. ALM treatment consisted of 1) a high dose bolus (A (0.82 mg/kg), L (1.76 mg/kg), M (0.92 mg/kg)), 2) one hour continuous infusion (A (300 µg ∙ kg(-1) ∙ min(-1)), L (600 µg ∙ kg(-1) ∙ min(-1)), M (336 µg ∙ kg(-1) ∙ min(-1))) and three hours at a lower dose (A (240 ∙ kg(-1) ∙ min(-1)), L (480 µg ∙ kg(-1) ∙ min(-1)), M (268 µg ∙ kg(-1) ∙ min(-1))); controls received normal saline. Hemodynamic, cardiac, pulmonary, metabolic and renal functions were evaluated. RESULTS: ALM lowered mean arterial pressure (Mean value during infusion period: ALM: 47 (95% confidence interval (CI): 44 to 50) mmHg versus control: 79 (95% CI: 75 to 85) mmHg, P < 0.0001). After cessation of ALM, mean arterial pressure immediately increased (end of study: ALM: 88 (95% CI: 81 to 96) mmHg versus control: 86 (95% CI: 79 to 94) mmHg, P = 0.72). Whole body oxygen consumption was significantly reduced during ALM infusion (ALM: 205 (95% CI: 192 to 217) ml oxygen/min versus control: 231 (95% CI: 219 to 243) ml oxygen/min, P = 0.016). ALM treatment reduced pulmonary injury evaluated by PaO2/FiO2 ratio (ALM: 388 (95% CI: 349 to 427) versus control: 260 (95% CI: 221 to 299), P = 0.0005). ALM infusion led to an increase in heart rate while preserving preload recruitable stroke work. Creatinine clearance was significantly lower during ALM infusion but reversed after cessation of infusion. ALM reduced tumor necrosis factor-α peak levels (ALM 7121 (95% CI: 5069 to 10004) pg/ml versus control 11596 (95% CI: 9083 to 14805) pg/ml, P = 0.02). CONCLUSION: ALM infusion induces a reversible hypotensive and hypometabolic state, attenuates tumor necrosis factor-α levels and improves cardiac and pulmonary function, and led to a transient drop in renal function that was reversed after the treatment was stopped.

Small-volume 7.5% NaCl adenosine, lidocaine, and Mg2+ has multiple benefits during hypotensive and blood resuscitation in the pig following severe blood loss: rat to pig translation.

OBJECTIVES: Currently, there is no effective small-volume fluid for traumatic hemorrhagic shock. Our objective was to translate small-volume 7.5% NaCl adenosine, lidocaine, and Mg hypotensive fluid resuscitation from the rat to the pig. DESIGN: Pigs (35-40 kg) were anesthetized and bled to mean arterial pressure of 35-40 mm Hg for 90 minutes, followed by 60 minutes of hypotensive resuscitation and infusion of shed blood. Data were collected continuously. SETTING: University hospital laboratory. SUBJECTS: Female farm-bred pigs. INTERVENTIONS: Pigs were randomly assigned to a single IV bolus of 4 mL/kg 7.5% NaCl + adenosine, lidocaine and Mg (n = 8) or 4 mL/kg 7.5% NaCl (n = 8) at hypotensive resuscitation and 0.9% NaCl ± adenosine and lidocaine at infusion of shed blood. MEASUREMENTS AND MAIN RESULTS: At 60 minutes of hypotensive resuscitation, treatment with 7.5% NaCl + adenosine, lidocaine, and Mg generated significantly higher mean arterial pressure (48 mm Hg [95% CI, 44-52] vs 33 mm Hg [95% CI, 30-36], p < 0.0001), cardiac index (76 mL/min/kg [95% CI, 63-91] vs 47 mL/min/kg [95% CI, 39-57], p = 0.002), and oxygen delivery (7.6 mL O2/min/kg [95% CI, 6.4-9.0] vs 5.2 mL O2/min/kg [95% CI, 4.4-6.2], p = 0.003) when compared with controls. Pigs that received adenosine, lidocaine, and Mg/adenosine and lidocaine also had significantly lower blood lactate (7.1 mM [95% CI, 5.7-8.9] vs 11.3 mM [95% CI, 9.0-14.1], p = 0.004), core body temperature (39.3°C [95% CI, 39.0-39.5] vs 39.7°C [95% CI, 39.4-39.9]), and higher base excess (-5.9 mEq/L [95% CI, -8.0 to -3.8] vs -11.2 mEq/L [95% CI, -13.4 to -9.1]). One control died from cardiovascular collapse. Higher cardiac index in the adenosine, lidocaine, and Mg/adenosine and lidocaine group was due to a two-fold increase in stroke volume. Left ventricular systolic ejection times were significantly higher and inversely related to heart rate in the adenosine, lidocaine, and Mg/adenosine and lidocaine group. Thirty minutes after blood return, whole-body oxygen consumption decreased in pigs that received adenosine, lidocaine, and Mg/adenosine and lidocaine (5.7 mL O2/min/kg [95% CI, 4.7-6.8] to 4.9 mL O2/min/kg [95% CI, 4.2-5.8]), whereas it increased in controls (4.2 mL O2/min/kg [95% CI, 3.5-5.0] to 5.8 mL O2/min/kg [95% CI, 4.9-5.8], p = 0.02). After 180 minutes, pigs in the adenosine, lidocaine, and Mg/adenosine and lidocaine group had three-fold higher urinary output (2.1 mL//kg/hr [95% CI, 1.2-3.8] vs 0.7 mL//kg/hr [95% CI, 0.4-1.2], p = 0.001) and lower plasma creatinine levels. CONCLUSION: Small-volume resuscitation with 7.5% NaCl + adenosine, lidocaine, and Mg/adenosine and lidocaine provided superior cardiovascular, acid-base, metabolic, and renal recoveries following severe hemorrhagic shock in the pig compared with 7.5% NaCl alone.

Automatic detection of left and right ventricles from CTA enables efficient alignment of anatomy with myocardial perfusion data.

BACKGROUND: Accurate alignment between cardiac CT angiographic studies (CTA) and nuclear perfusion images is crucial for improved diagnosis of coronary artery disease. This study evaluated in an animal model the accuracy of a CTA fully automated biventricular segmentation algorithm, a necessary step for automatic and thus efficient PET/CT alignment. METHODS AND RESULTS: Twelve pigs with acute infarcts were imaged using Rb-82 PET and 64-slice CTA. Post-mortem myocardium mass measurements were obtained. Endocardial and epicardial myocardial boundaries were manually and automatically detected on the CTA and both segmentations used to perform PET/CT alignment. To assess the segmentation performance, image-based myocardial masses were compared to experimental data; the hand-traced profiles were used as a reference standard to assess the global and slice-by-slice robustness of the automated algorithm in extracting myocardium, LV, and RV. Mean distances between the automated and the manual 3D segmented surfaces were computed. Finally, differences in rotations and translations between the manual and automatic surfaces were estimated post-PET/CT alignment. The largest, smallest, and median distances between interactive and automatic surfaces averaged 1.2 ± 2.1, 0.2 ± 1.6, and 0.7 ± 1.9 mm. The average angular and translational differences in CT/PET alignments were 0.4°, -0.6°, and -2.3° about x, y, and z axes, and 1.8, -2.1, and 2.0 mm in x, y, and z directions. CONCLUSIONS: Our automatic myocardial boundary detection algorithm creates surfaces from CTA that are similar in accuracy and provide similar alignments with PET as those obtained from interactive tracing. Specific difficulties in a reliable segmentation of the apex and base regions will require further improvements in the automated technique.

Hyperkalemic cardioplegia for adult and pediatric surgery: end of an era?

Despite surgical proficiency and innovation driving low mortality rates in cardiac surgery, the disease severity, comorbidity rate, and operative procedural difficulty have increased. Today's cardiac surgery patient is older, has a "sicker" heart and often presents with multiple comorbidities; a scenario that was relatively rare 20 years ago. The global challenge has been to find new ways to make surgery safer for the patient and more predictable for the surgeon. A confounding factor that may influence clinical outcome is high K(+) cardioplegia. For over 40 years, potassium depolarization has been linked to transmembrane ionic imbalances, arrhythmias and conduction disturbances, vasoconstriction, coronary spasm, contractile stunning, and low output syndrome. Other than inducing rapid electrochemical arrest, high K(+) cardioplegia offers little or no inherent protection to adult or pediatric patients. This review provides a brief history of high K(+) cardioplegia, five areas of increasing concern with prolonged membrane K(+) depolarization, and the basic science and clinical data underpinning a new normokalemic, "polarizing" cardioplegia comprising adenosine and lidocaine (AL) with magnesium (Mg(2+)) (ALM™). We argue that improved cardioprotection, better outcomes, faster recoveries and lower healthcare costs are achievable and, despite the early predictions from the stent industry and cardiology, the "cath lab" may not be the place where the new wave of high-risk morbid patients are best served.

The effects of adenocaine (adenosine and lidocaine) on early post-resuscitation cardiac and neurological dysfunction in a porcine model of cardiac arrest.

AIM: Return of spontaneous circulation (ROSC) elicits ischaemia/reperfusion injury and myocardial dysfunction. The combination of adenosine and lidocaine (AL, adenocaine) has been shown to (1) inhibit neutrophil inflammatory activation and (2) improve left ventricular function after ischaemia. We hypothesized that resuscitation with adenocaine during early moments of cardiopulmonary resuscitation (CPR) attenuates leucocyte oxidant generation and myocardial dysfunction. METHODS: Pigs were randomized to: (1) sham (n=7), (2) cardiac arrest (CA; n=16), or 3) cardiac arrest+adenocaine (CA+AL; n=12). After 7 min of electrically induced ventricular fibrillation, start of CPR was followed by infusion of saline (CA) or adenocaine (CA+AL) for 6 min. Haemodynamics, cardiodynamics (pressure-volume loops) and leucocyte superoxide anion generation were assessed. Neurological function was evaluated after 24h by histology and neurological deficit score (0=normal; 500=brain dead). RESULTS: Rate of ROSC was comparable between groups: CA group 11/16 and CA+AL group 7/12 p=0.57). Cardiac index transiently increased after ROSC in both groups. Left ventricular dysfunction demonstrated by a rightward shift of the intercept of end-systolic pressure-volume relations in CA was avoided in the CA+AL group. Leucocyte superoxide anion generation 2h after ROSC was significantly attenuated in the CA+AL group compared to the CA group. Neurological deficit scores [CA: median: 17.5(IQR:0-75) and CA+AL: 35(IQR:15-150)] and histopathological damage were comparable in both groups (p=0.37). CONCLUSION: Infusion of adenocaine during early resuscitation from CA significantly improved early post-resuscitation cardiac function and attenuated leucocyte superoxide anion generation, without a change in post-ROSC neurological function. (IACUC protocol number 023-2009).

Postconditioning attenuates acute intestinal ischemia-reperfusion injury.

The aim of this study was to test the hypothesis that postconditioning (POC) would reduce the detrimental effects of the acute intestinal ischemia-reperfusion (I/R) compared to those of the abrupt onset of reperfusion. POC has a protective effect on intestinal I/R injury by inhibiting events in the early minutes of reperfusion in rats. Twenty-four Wistar-Albino rats were subjected to the occlusion of superior mesenteric artery for 30 minutes, then reperfused for 120 minutes, and randomized to the four different modalities of POC: (1) control (no intervention); (2) POC-3 (three cycles of 10 seconds of reperfusion-reocclusion, 1 minute total intervention); (3) POC-6 (six cycles of 10 seconds of reperfusion-reocclusion, 2 minutes total intervention); and (4) sham operation (laparotomy only). The arterial blood samples [0.3 mL total creatine kinase (CK) and 0.6 mL malondialdehyde (MDA)] and the intestinal mucosal MDA were collected from each after reperfusion. POC, especially POC-6, was effective in attenuating postischemic pathology by decreasing the intestinal tissue MDA levels, serum total CK activity, inflammation, and total histopathological injury scores. POC exerted a protective effect on the intestinal mucosa by reducing the mesenteric oxidant generation, lipid peroxidation, and neutrophil accumulation. The six-cycle algorithm demonstrated the best protection.

The science and clinical translation of remote postconditioning.

The treatment of reperfusion injury requires measures beyond timely reperfusion. Conventional postconditioning (PostC) of ischemic tissues offers a strategy to reduce reperfusion injury, but its adoption is challenged by requiring access and imposing additional ischemia to the ischemic organ. Generating protective signals by PostC in a tissue remote from the target organ such as the limb, i.e. remote PostC (rPostC), may present an alternative approach to exerting endogenous tissue protection. Because rPostC is only recently reported, the fundamental biology of rPostC is not well understood, and studies to date are largely observational. rPostC has been observed to reduce ischemia-reperfusion injury experimentally in heart, kidney, brain and skeletal muscle in multiple species, including rat, rabbit and pig. Both necrosis and apoptosis are reduced. As in remote ischemic preconditioning, rPostC requires a transfer or communication of protective factors or signals through humoral and/or neural pathways. Triggers of target organ protection include G-protein-coupled receptor ligands, metabolites of ischemia, or small thermolabile molecules. Some evidence suggests that reperfusion injury salvage kinases may be involved in rPostC, in agreement with both preconditioning and conventional PostC. Clinical studies investigating improvements in clinical outcomes or biomarkers with rPostC are encouraging.