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BACKGROUND Donation after circulatory death (DCD) represents an increasing source of organs. However, evaluating the suitability of DCD hearts for transplantation represents a challenge. Contractile function is the ultimate determinant of recovery. We developed a novel technique in an ex vivo rig for the measurement of contractility using intraventricular balloons. We compared this technique with the measurement of lactate metabolism, the current gold standard. METHODS Human DCD (n = 6) and donation after brain death (n = 6) hearts were preserved by perfusion with a cold oxygenated crystalloid solution for 4 h, transferred to a blood perfusion rig at 37 °C where balloons were inserted into the left (LV) and right (RV) ventricles to measure developed pressure (DP = systolic minus diastolic). Perfusate lactate levels were measured for metabolic assessment. Concordance between LVDP and lactate was assessed during 4 h using cutoffs for LVDP of 70 mm Hg and for lactate of 10 mmol/L. RESULTS Measurements of contractile function (LVDP) and metabolism (lactate levels) were deemed concordant in 7 hearts with either a high LVDP (mean 100 mm Hg) with low lactate (mean 6.7 mmol/L)) or a low LVDP (15 mm Hg) with high lactate (mean 17.3 mmol/). In the remaining 5 hearts, measurements were deemed discordant: 4 hearts had high LVDP (mean 124 mm Hg), despite high lactate levels 17.3 mmol/L) and 1 had low LVDP (54 mm Hg) but low lactate (6.9 mmol/L). CONCLUSIONS The intraventricular balloon technique provides useful information regarding contractile recovery of donor hearts that if combined with lactate metabolism has potential application for the evaluation of DCD and marginal donation after brain death hearts before transplant.

Several biological mechanisms have been proposed to account for age-related cognitive decline including cerebrovascular disease, mitochondrial dysfunction, inflammation, impaired neuronal signaling, and reduced antioxidant capacity. Oxidative stress has been well studied although more intervention trials are needed. A limited number of clinical trials using nutraceuticals to target oxidative stress and improve cognitive function have been undertaken. Of these, the most promising interventions are Coenzyme Q10 (CoQ10), pycnogenol, and the nonflavonoid polyphenols, curcumin, and resveratrol. This chapter discusses some of the mechanisms underlying cognitive aging, with a particular focus on oxidative stress and reviews the efficacy and mechanisms by which nutraceuticals improve cognitive function. We conclude that while there is some evidence that nutraceuticals with antioxidant activity may reduce cognitive decline, and that there are plausible biological mechanisms by which this may occur, large and long-term clinical trials are lacking and results are somewhat inconsistent. A recently completed trial completed by our group, the Australian Research Council Longevity Intervention, may shed some light on this topic.

Background Use of donation after circulatory death (DCD) hearts is becoming more prevalent in cardiac transplantation. However, there is no standardized approach to myocardial preservation, and little data exists on ultrastructural changes in DCD hearts. We have previously identified increased proapoptotic and proinflammatory activity in brain dead donor (BDD) hearts that subsequently exhibit primary graft failure and lower levels in DCD left atrial tissue. This study further investigates these markers and correlates them with cardiac function in DCD hearts. Methods This prospective study used donor hearts deemed unsuitable for transplant after gaining institutional ethics approval; 11 human hearts were obtained from 5 DCD donors and 6 BDDs. All hearts were preserved by continuous microperfusion for 4 hours with a cold crystalloid solution and then were evaluated on a blood perfusion bench rig. After 4 hours perfusion and working assessment, tissues from all cardiac chambers were stored for later messenger RNA (mRNA) analysis for proapoptotic and proinflammatory markers. Results Significantly raised levels of caspase-1, BNIP3, and NADPH oxidase mRNA expression were identified in cardiac chambers from BDD hearts compared to DCD hearts, and these differences were exaggerated in older donors. In the pooled analysis, lower expression of caspase-1, NF-κB1, and BNIP3 mRNA correlated with developed pressure at 1 hour after reperfusion in the right ventricle, but not the left. Conclusion Compared to BDD hearts, DCD hearts exhibit less stimulation of proapoptotic cascades and reactive oxygen species, potentially reducing their susceptibility to ischemic reperfusion injury.

The aim of this study was to define the status of preoperative zinc levels in patients with heart disease presenting for cardiac surgery and to identify any predictors for and any clinical consequences of low zinc levels.Adult patients presenting for elective surgery, either coronary artery bypass graft surgery and/or valve replacement, provided a fasting blood sample on the day of admission for surgery. Plasma and erythrocyte zinc levels were analysed and the levels correlated with the patient's characteristics and clinical outcomes.Of 56 patients 53% (n=30) had abnormally low plasma zinc levels (12μmol/L) and 5.5% (n=3) had abnormally low erythrocyte zinc levels (160μmol/L), indicative of deficiency. There were significant associations between lower plasma zinc levels and the presence of hypertension (p=0.02), hypercholesteraemia (p=0.02) and higher body mass index (BMI) (p=0.034) but no effect on major postoperative clinical outcomes.This small study shows that zinc deficiency is common in cardiac surgery patients, especially in the presence of hypertension, hypercholesterolaemia or obesity. The effects of zinc deficiency in cardiac surgery need to be further investigated.

Introduction: With an aging population there is an important need for the development of effective treatments for the amelioration of cognitive decline. Multiple mechanisms underlie age-related cognitive decline including cerebrovascular disease, oxidative stress, reduced antioxidant capacity and mitochondrial dysfunction. CoQ10 is a novel treatment which has the potential to improve brain function in healthy elderly populations due to established beneficial effects on mitochondrial function, vascular function and oxidative stress. Methods and Analysis: We describe the protocol for a 90-day randomized controlled trial which examines the efficacy of Ubiquinol (200 mg/day) vs. placebo for the amelioration of cognitive decline in a healthy (non-demented) elderly sample, aged 60 years and over. The primary outcome is the effect of Ubiquinol at 90 days compared to baseline on CogTrack composite measures of cognition. Additional cognitive measures, as well as measures of cardiovascular function, oxidative stress, liver function and mood will also be monitored across 30-, 60- and 90- day time points. Data analyses will involve repeated measures analysis of variance (ANOVA). Discussion: This study will be the first of its kind to provide important clinical and mechanistic data regarding the efficacy of Ubiquinol as a treatment for age-related cognitive decline in the healthy elderly with important implications for productivity and quality of life within this age group. Clinical Trial Registration: The trial has been registered with the Australian and New Zealand Clinical Trials Registry (ANZCTRN12618001841268).

Statin drugs have become the most highly prescribed drugs for cardiovascular disease. However, there is disagreement as to the existence of adverse effects of statin administration on cognitive function. Therefore, it is important to better understand the effects of statins on cognition and possible mechanisms of these effects. Areas covered: We analyzed relevant studies of the relationship between cognitive performance and statin and usage. We included articles published between 2018 and 1992. We identified three randomized trials, one observational study and 66 case reports that provided credible evidence of statin-induced cognitive impairment. We also identified seven randomized trials and two observational studies reporting no significant evidence of statin-induced cognitive impairment. Expert opinion: We found methodological differences that may have contributed to the divergence of these results. Evaluation of all these studies indicated that statin-associated cognitive decline is a real entity. Likely mechanisms to explain the adverse effects include 1. Reduction of synthesis of coenzyme Q

We previously showed that donation after circulatory death (DCD) canine hearts can be resuscitated if perfused with warm blood. However, clinical application of this technique is complex and difficult. We have developed a simplified system of cold crystalloid perfusion and compared it with standard cold storage for DCD heart preservation.Anesthetized greyhounds underwent 30 minutes DCD by withdrawal of ventilation followed by assignment to either 4 hours of perfusion (n = 6) or cold storage (n = 7). Nonpreserved hearts (n = 5) served as a normal reference group. Perfusion hearts were reperfused with a protective solution then perfused for 4 hours with a novel oxygenated, nutrient-containing solution at 20 mL/min at 4°C to 10°C. Cold storage hearts were flushed with St Thomas' cardioplegic solution and stored in ice. After preservation, the recovery of the hearts was assessed on a blood-perfused working heart rig.During preservation, perfusion hearts consumed oxygen (0.09 ± 0.01 mL/100 g per minute) and showed decreasing lactate production in the perfusate (initial: 0.031 ± 0.004 vs final: 0.007 ± 0.002 mmol/min; P = 0.001). After preservation, compared to cold storage hearts, perfusion hearts had higher cardiac output (P = 0.004), LV dP/dt max (P = 0.003) and myocardial oxygen efficiency (P = 0.01), with lower blood perfusate lactate (P = 0.007). Hemodynamic values of perfused hearts reached 60% or more those in the normal reference group.Continuous cold crystalloid perfusion in a canine model of DCD: (1) facilitates aerobic metabolism and resuscitates the DCD heart, (2) provides functional and metabolic recovery superior to cold storage, (3) shows promise for improved clinical preservation of DCD and marginal donor hearts.

Background Donation after circulatory death (DCD) represents a potential new source of hearts to increase the donor pool. We showed previously that DCD hearts in Greyhound dogs could be resuscitated and preserved by continuous cold crystalloid perfusion but not by cold static storage and could demonstrate excellent contractile and metabolic function on an in vitro system. In the current study, we demonstrate that resuscitated DCD hearts are transplantable. Methods Donor Greyhound dogs ( n = 12) were divided into perfusion ( n = 8) and cold static storage ( n = 4) groups. General anesthesia was induced and ventilation ceased for 30 minutes to achieve circulatory death. Donor cardiectomy was performed, and for 4 hours the heart was preserved by controlled reperfusion, followed by continuous cold perfusion with an oxygenated crystalloid perfusate or by static cold storage, after which orthotopic heart transplantation was performed. Recovery was assessed over 4 hours by hemodynamic monitoring. Results During cold perfusion, hearts showed continuous oxygen consumption and low lactate levels, indicating aerobic metabolism. The 8 dogs in the perfusion group were weaned off bypass, and 4 hours after bypass produced cardiac output of 4.73 ± 0.51 liters/min, left ventricular power of 7.63 ± 1.32 J/s, right ventricular power of 1.40 ± 0.43 J/s, and left ventricular fractional area shortening of 39.1% ± 5.2%, all comparable to pre-transplant values. In the cold storage group, 3 of 4 animals could not be weaned from cardiopulmonary bypass, and the fourth exhibited low-level function. Conclusions Cold crystalloid perfusion, but not cold static storage, can resuscitate and preserve the DCD donor heart in a canine model of heart transplantation, thus rendering it transplantable. Controlled reperfusion and cold crystalloid perfusion have potential for clinical application in DCD transplantation.

Despite increasing use of donation after cardiac death (DCD) and encouraging results for non-cardiac transplants, DCD cardiac transplantation has not been widely adopted because, (1) the DCD heart sustains warm ischaemic injury during the death process and (2) conventional static cold storage significantly adds to the ischaemic injury. We have developed a simple system for perfusion of the DCD heart with cold crystalloid solution using gravity-feed that can reduce ischaemic injury and potentially render the heart suitable for transplantation. This report describes the first application of this technique to a human DCD heart with good functional metabolic recovery over 12h on an ex vivo rig.

younger muscle. 4)Oral CoQ10 therapy before cardiac surgery improves efficiency of mitochondrial energy production, improves post-operative heart function, reduces intra-operative myocardial damage and shortens hospital stay.

Background Preservation of donor hearts for transplantation has traditionally been performed with the use of static cold storage. We have developed and tested a novel gravity-powered system of cold crystalloid perfusion for prolonged donor heart preservation. Methods Greyhounds were anesthetized; their hearts were arrested with cold cardioplegic solution and excised. Hearts were allocated to 12 hours of perfusion preservation ( n = 6) or cold storage in ice ( n = 5). Non-preserved hearts ( n = 5) served as a normal reference group. Perfusion hearts were perfused (20 mL/min, 8–12°C) with a novel oxygenated nutrient-containing preservation solution. After preservation, the recovery of the hearts was assessed in a blood-perfused working heart rig over 2 hours in terms of function, blood lactate level, myocardial adenosine triphosphate, and histology. Results After 2 hours of reperfusion, in comparison with cold storage hearts, perfused heart function curves showed superior recovery of cardiac output ( P = .001), power ( P = .001), and efficiency (0.046 ± 0.01 vs 0.004 ± 0.003 joules/mL O 2 , P = .034). Myocardial adenosine triphosphate content (mmol/mg protein) was reduced significantly from the normal level of 26.5 (15.9, 55.8) to 5.08 (0.50, 10.4) ( P = .049) in cold storage hearts but not in perfused hearts. Over a period of 2 hours, lactate levels in the blood perfusate were significantly lower in the perfusion group than in the cold storage group ( P Conclusions Continuous hypothermic crystalloid perfusion provides myocardial preservation superior to cold storage for long-term heart preservation, with potential applicability to marginal and donation after circulatory death hearts.

The protective effect of University of Wisconsin solution (UW) for hypothermic storage of donor hearts has been demonstrated in the laboratory. However, clinical usage is associated with occasional primary graft failures. We postulated that this could be related to adverse effects of UW on the coronary vasculature during cardiac implantation and rewarming. We therefore assessed recovery of contractile function and coronary flow in rat hearts after cardioplegic arrest using UW compared with St. Thomas' solution (ST) at 4 degrees C or 25 degrees C.Cardioplegia was induced in isolated rat hearts using either UW or ST at 4 degrees C. Hearts were then maintained at 4 degrees C or 25 degrees C. In some hearts, UW at 4 degrees C was used for inducing arrest followed by flushing with ST at 4 degrees C and then rewarming to 25 degrees C. After 40 minutes of arrest, recovery of function and coronary flow were measured. Nuclear track emulsion was used to assess microvascular competence.Compared with ST-treated hearts, UW-treated hearts showed significant reduction in recovery of function at 25 degrees C (76.2% +/- 4.0% versus 25.0% +/- 4.1%; p0.01) but not at 4 degrees C (88.0% +/- 1.6% versus 87.1% +/- 2.6%). Recovery of coronary flow in the UW-treated hearts at 25 degrees C was significantly lower than that in the ST-treated hearts at 25 degrees C (71.7% +/- 3.0% versus 94.5% +/- 6.3%; p0.01). At 25 degrees C, microvascular competence was reduced in the UW group compared with the ST group. At 25 degrees C, flushing out UW with ST resulted in greater recovery of function compared with UW throughout (73.4% +/- 7.1% versus 25.0% +/- 4.1%; p0.01).University of Wisconsin solution provides effective donor heart protection under hypothermic conditions but can be deleterious at warmer temperatures.

The inferior recovery of cardiac function after interventional cardiac procedures in elderly patients compared to younger patients suggests that the aged myocardium is more sensitive to stress. We report two studies that demonstrate an age-related deficit in myocardial performance after aerobic and ischemic stress and the capacity of CoQ10 treatment to correct age-specific diminished recovery of function. In Study 1 the functional recovery of young (4 mo) and senescent (35 mo) isolated working rat hearts after aerobic stress produced by rapid electrical pacing was examined. After pacing, the senescent hearts, compared to young, showed reduced recovery of pre-stress work performance. CoQ10 pretreatment (daily intraperitoneal injections of 4 mg/kg CoQ10 for 6 weeks) in senescent hearts improved their recovery to match that of young hearts. Study 2 tested whether the capacity of human atrial trabeculae (obtained during surgery) to recover contractile function, following ischemic stress in vitro (60 min), is decreased with age and whether this decrease can be reversed by CoQ10. Trabeculae from older individuals (or = 70 yr) showed reduced recovery of developed force after simulated ischemia compared to younger counterparts (70 yr). Notably, this age-associated effect was prevented in trabeculae pretreated in vitro (30 min at 24 degrees C) with CoQ10 (400 MicroM). We measured significantly lower CoQ10 content in trabeculae fromor = 70 yr patients. In vitro pretreatment raised trabecular CoQ10 content to similar levels in all groups. We conclude that, compared to younger counterparts, the senescent myocardium of rats and humans has a reduced capacity to tolerate ischemic or aerobic stress and recover pre-stress contractile performance, however, this reduction is attenuated by CoQ10 pretreatment.

Reactive oxygen species (ROS) play both physiological and pathophysiological roles in the body. In clinical practice, oxidative stress and its counterpart, antioxidant capacity, can be measured and can guide remedial therapy. Oxidative stress can make a negative impact in all forms of major surgery including cardiac surgery, general surgery, trauma surgery, orthopedic surgery, and plastic surgery. Many and various therapies aimed at reducing oxidative stress in surgery have been tried with variable results. We conclude that in surgical patients, the assessment of oxidative stress, improving understanding of its role, both positive and negative, and devising appropriate therapies are of great clinical importance and represent fruitful fields for further research.

Irreversible electroporation (IRE) is a non-thermal focal ablation technique that uses needle electrodes to deliver a series of brief (100μs duration) electric pulses into the targeted region. These alter cellular transmembrane potentials, destabilizing the membranes in a manner that kills the cells while sparing major vasculature and other sensitive structures. IRE can therefore be used in regions ineligible for surgical resection or thermal ablation. Treatments result in rapid lesion creation and resolution [1], are unaffected by the blood perfusion “heat sink”, can be planned with numerical modeling [2], and its effects can be readily monitored with various imaging modalities [3]. Therapeutic ire has proven effective in the treatment of experimental [4] and clinical tumors. A human safety study attained complete regression in 46 of 69 tumors ineligible or unresponsive to conventional treatment [5], and veterinary case studies convey its utility in large difficult tumors [6, 7].Copyright © 2013 by ASME

Electroporation-based therapies deliver brief electric pulses into a targeted volume to destabilize cellular membranes. Nonthermal irreversible electroporation (IRE) provides focal ablation with effects dependent on the electric field distribution, which changes in heterogeneous environments. It should be determined if highly conductive metallic implants in targeted regions, such as radiotherapy brachytherapy seeds in prostate tissue, will alter treatment outcomes. Theoretical and experimental models determine the impact of prostate brachytherapy seeds on IRE treatments. This study delivered IRE pulses in nonanimal, as well as in ex vivo and in vivo tissue, with and in the absence of expired radiotherapy seeds. Electrical current was measured and lesion dimensions were examined macroscopically and with magnetic resonance imaging. Finite-element treatment simulations predicted the effects of brachytherapy seeds in the targeted region on electrical current, electric field, and temperature distributions. There was no significant difference in electrical behavior in tissue containing a grid of expired radiotherapy seeds relative to those without seeds for nonanimal, ex vivo, and in vivo experiments (all p > 0.1). Numerical simulations predict no significant alteration of electric field or thermal effects (all p > 0.1). Histology showed cellular necrosis in the region near the electrodes and seeds within the ablation region; however, there were no seeds beyond the ablation margins. This study suggests that electroporation therapies can be implemented in regions containing small metallic implants without significant changes to electrical and thermal effects relative to use in tissue without the implants. This supports the ability to use IRE as a salvage therapy option for brachytherapy.

Reactive oxygen species (ROS) play an important role in the regulation of normal cellular function. When ROS are produced in excess they can have detrimental effects, a state known as oxidative stress. Thus ROS play both physiological and pathophysiological roles in the body. In clinical practice oxidative stress and its counterpart, antioxidant capacity can be measured and can guide remedial therapy. Oxidative stress can have a negative impact in all forms of major surgery including cardiac surgery, general surgery, trauma surgery, orthopedic surgery and plastic surgery; this is particularly marked in an ageing population. Many different therapies to reduce oxidative stress in surgery have been tried with variable results. We conclude that in surgical patients the assessment of oxidative stress, improvement of the understanding of its role, both positive and negative, and devising appropriate therapies represent fruitful fields for future research.

Ca(2+) overload plays an important role in the pathogenesis of cardioplegic ischemia-reperfusion injury. The standard technique to control Ca(2+) overload has been to reduce Ca(2+) in the cardioplegic solution (CP). Recent reports suggest that Na(+)/H(+) exchange inhibitors can also prevent Ca(2+) overload. We compared 4 crystalloid CPs that might minimize Ca(2+) overload in comparison with standard Mg(2+)-containing CP: (1) low Ca(2+) CP (0.25 mmol/L), (2) citrate CP/normal Mg(2+) (1 mmol/L Mg(2+)), (3) citrate CP/high Mg(2+) (9 mmol/L Mg(2+)), and (4) the addition of the Na(+)/H(+) exchange inhibitor HOE-642 (Cariporide). We also tested the effect of citrate titration in vitro on the level of free Ca(2+) and Mg(2+) in CPs.Isolated working rat heart preparations were perfused with oxygenated Krebs-Henseleit buffer and subjected to 60 minutes of 37 degrees C arrest and reperfusion with CPs with different Ca(2+) concentrations. Cardiac performance, including aortic flow (AF), was measured before and after ischemia. Myocardial high-energy phosphates were measured after reperfusion. The in vitro addition of citrate to CP (2%, 21 mmol/L) produced parallel reductions in Mg(2+) and Ca(2+). Because only Ca(2+) was required to be low, the further addition of Mg(2+) increased free Mg(2+), but the highest level achieved was 9 mmol/L. Citrate CP significantly impaired postischemic function (AF 58.3+/-2. 5% without citrate versus 41.6+/-3% for citrate with normal Mg(2+), P:0.05, versus 22.4+/-6.2% for citrate with high Mg(2+), P:0.05). Low-Ca(2+) CP (0.25 mmol/L Ca(2+)) significantly improved the recovery of postischemic function in comparison with standard CP (1.0 mmol/L Ca(2+)) (AF 47.6+/-1.7% versus 58.3+/-2.5%, P:0.05). The addition of HOE-642 (1 micromol/L) to CP significantly improved postischemia function (47.6+/-1.7% without HOE-642 versus 62.4+/-1. 7% with HOE-642, P:0.05). Postischemia cardiac high-energy phosphate levels were unaffected by Ca(2+) manipulation.(1) A lowered Ca(2+) concentration in CP is beneficial in Mg(2+)-containing cardioplegia. (2) The use of citrate to chelate Ca(2+) is detrimental in the crystalloid-perfused isolated working rat heart, especially with high Mg(2+). (3) The mechanism of citrate action is complex, and its use limits precise simultaneous control of Ca(2+) and Mg(2+). (4) HOE-642 in CP is as efficacious in preservation of the ischemic myocardium as is the direct reduction in Ca(2+).

Purpose: Epidemiological studies demonstrated that particulate air pollution (PM) can trigger adverse health effects. We demonstrated that chronic exposure to air pollution is associated with increased risk of chronic rejection and mortality after lung transplantation (LTx). In the present study, we investigated whether short-term elevations in PM10 increased the risk of acute rejection after LTx.

Background: Recovery of cardiac function after cardiac surgery and other interventional cardiac procedures in elderly patients is inferior to that in younger patients, suggesting that the aged myocardium is more sensitive to ischemia and other stresses. Although convincing data from animal studies of senescence now exist, there is a dearth of controlled in vitro studies that examine the specific response of aged human myocardium to the stress of hypoxia or ischemia. Objective: We sought to determine the effect of age on the capacity of human atrial trabeculae to recover contractile function after in vitro hypoxic or ischemic stress. Methods: Atrial pectinate trabeculae were dissected from the tip of 58 right atrial appendages harvested during an operation in patients aged between 34 and 89 years and electrically stimulated at 1 Hz in oxygenated Ringer's solution at 37°C. Tissues experienced 30 minutes of either hypoxia (N 2 and perfusate) or simulated ischemia (humidified N 2 without perfusate) and were returned to normoxia for recovery of function for 30 minutes. Developed force and other contractile variables were determined during each period. Results: Under normoxic conditions, no significant age difference was observed for any contractile function variable. However, after hypoxia, the old (70-89 years) and intermediate age groups (60-69 years) showed reduced recovery of developed force (48.5% ± 22.2% [n = 11] and 44.9% ± 19% [n = 12], respectively) compared with that found (66.4% ± 19.7% [n = 15]) in the younger (34-59 years) group (mean ± SD, P = .02). Similarly, after simulated ischemia, the groups of 70- to 89-year-old and 60- to 69-year-old subjects showed reduced recovery of developed force (35.7% ± 17% [n = 5] and 51.1% ± 11.8% [n = 9], respectively) compared with that found (68.2% ± 10.4% [n = 6]) in the group of 34- to 59-year-old subjects ( P = .01). Multivariable analysis, comparing 20 factors of surgical patient characteristics and recovery of developed force, found that only age ( P = .01) and hypertension ( P = .01) were predictors of reduced recovery of developed force after either hypoxia or simulated ischemia. Conclusions: In aged human atrial myocardium, the capacity to recover contractile function after in vitro hypoxia or simulated ischemia is reduced compared with the younger myocardium of mature adults. These findings suggest that enhanced myocardial protective strategies may be indicated for elderly patients undergoing cardiac surgery. (J Thorac Cardiovasc Surg 2000;120:660-7)