| 1. |
- Li, Mei, et al.
(författare)
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Development and prevention of ischemic contracture (“stone heart”) in the pig heart
- 2023
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Ingår i: Frontiers in Cardiovascular Medicine. - : Frontiers Media SA. - 2297-055X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Stone heart (ischemic contracture) is a rare and serious condition observed in the heart after periods of warm ischemia. The underlying mechanisms are largely unknown and treatment options are lacking. In view of the possibilities for cardiac donation after circulatory death (DCD), introducing risks for ischemic damage, we have investigated stone heart in pigs. Following cessation of ventilation, circulatory death (systolic pressure <8 mmHg) occurred within 13.1 ± 1.2 min; and a stone heart, manifested with asystole, increased left ventricular wall thickness and stiffness, established after a further 17 ± 6 min. Adenosine triphosphate and phosphocreatine levels decreased by about 50% in the stone heart. Electron microscopy showed deteriorated structure with contraction bands, Z-line streaming and swollen mitochondria. Synchrotron based small angle X-ray scattering of trabecular samples from stone hearts revealed attachment of myosin to actin, without volume changes in the sarcomeres. Ca2+ sensitivity, determined in permeabilized muscle, was increased in stone heart samples. An in vitro model for stone heart, using isolated trabecular muscle exposed to hypoxia/zero glucose, exhibited the main characteristics of stone heart in whole animals, with a fall in high-energy phosphates and development of muscle contracture. The stone heart condition in vitro was significantly attenuated by the myosin inhibitor MYK-461 (Mavacamten). In conclusion, the stone heart is a hypercontracted state associated with myosin binding to actin and increased Ca2+ sensitivity. The hypercontractile state, once developed, is poorly reversible. The myosin inhibitor MYK-461, which is clinically approved for other indications, could be a promising venue for prevention.
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| 2. |
- Arlock, Per, et al.
(författare)
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Excitation and contraction of cardiac muscle and coronary arteries of brain-dead pigs
- 2023
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Ingår i: FASEB BioAdvances. - : Wiley. - 2573-9832. ; 5:2, s. 71-84
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Tidskriftsartikel (refereegranskat)abstract
- Excitability and contraction of cardiac muscle from brain-dead donors critically influence the success of heart transplantation. Membrane physiology, Ca2+-handling, and force production of cardiac muscle and the contractile properties of coronary arteries were studied in hearts of brain-dead pigs. Cardiac muscle and vascular function after 12 h brain death (decapitation between C2 and C3) were compared with properties of fresh tissue. In both isolated cardiomyocytes (whole-cell patch clamp) and trabecular muscle (conventional microelectrodes), action potential duration was shorter in brain dead, compared to controls. Cellular shortening and Ca2+ transients were attenuated in the brain dead, and linked to lower mRNA expression of L-type calcium channels and a slightly lower ICa,L, current, as well as to a lower expression of phospholamban. The current–voltage relationship and the current above the equilibrium potential of the inward K+ (IK1) channel were altered in the brain-dead group, associated with lower mRNA expression of the Kir2.2 channel. Delayed K+ currents were detected (IKr, IKs) and were not different between groups. The transient outward K+ current (Ito) was not observed in the pig heart. Coronary arteries exhibited increased contractility and sensitivity to the thromboxane analogue (U46619), and unaltered endothelial relaxation. In conclusion, brain death involves changes in cardiac cellular excitation which might lower contractility after transplantation. Changes in the inward rectifier K+ channel can be associated with an increased risk for arrhythmia. Increased reactivity of coronary arteries may lead to increased risk of vascular spasm, although endothelial relaxant function was well preserved.
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| 3. |
- Längin, Matthias, et al.
(författare)
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Xenografts Show Signs of Concentric Hypertrophy and Dynamic Left Ventricular Outflow Tract Obstruction after Orthotopic Pig-to-baboon Heart Transplantation
- 2023
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Ingår i: Transplantation. - 0041-1337. ; 107:12, s. 328-338
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Tidskriftsartikel (refereegranskat)abstract
- Background. Orthotopic cardiac xenotransplantation has seen substantial advancement in the last years and the initiation of a clinical pilot study is close. However, donor organ overgrowth has been a major hurdle for preclinical experiments, resulting in loss of function and the decease of the recipient. A better understanding of the pathogenesis of organ overgrowth after xenotransplantation is necessary before clinical application. Methods. Hearts from genetically modified (GGTA1-KO, hCD46/hTBM transgenic) juvenile pigs were orthotopically transplanted into male baboons. Group I (control, n = 3) received immunosuppression based on costimulation blockade, group II (growth inhibition, n = 9) was additionally treated with mechanistic target of rapamycin inhibitor, antihypertensive medication, and fast corticoid tapering. Thyroid hormones and insulin-like growth factor 1 were measured before transplantation and before euthanasia, left ventricular (LV) growth was assessed by echocardiography, and hemodynamic data were recorded via a wireless implant. Results. Insulin-like growth factor 1 was higher in baboons than in donor piglets but dropped to porcine levels at the end of the experiments in group I. LV mass increase was 10-fold faster in group I than in group II. This increase was caused by nonphysiological LV wall enlargement. Additionally, pressure gradients between LV and the ascending aorta developed, and signs of dynamic left ventricular outflow tract (LVOT) obstruction appeared. Conclusions. After orthotopic xenotransplantation in baboon recipients, untreated porcine hearts showed rapidly progressing concentric hypertrophy with dynamic LVOT obstruction, mimicking hypertrophic obstructive cardiomyopathy in humans. Antihypertensive and antiproliferative drugs reduced growth rate and inhibited LVOT obstruction, thereby preventing loss of function.
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| 4. |
- Persson, G. Rutger, et al.
(författare)
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Impact of an Okinawa/Nordic based diet on endocrinological and periodontal conditions in individuals with type 2 diabetes. A randomized case–control study
- 2023
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Ingår i: BMC Oral Health. - : BioMed Central Ltd.. - 1472-6831. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To assess if the results following intake of a diet using an Okinawan-based Nordic diet (OBND) over one month differs in endocrinological, periodontal clinical outcome, and serum cytokine levels compared to a standard hospital care diet in individuals with diabetes type 2 (T2D) (control group). Background: Scientific evidence suggests that the use of diet for individuals with T2D may be beneficial. Methods: Participating individuals with T2D were randomly assigned to a test (OBND) (n = 14), or control group (n = 16). Anthropometric data, blood glucose levels, HbA1c levels, lipids, serum inflammation markers (CRP, and a routine panel of 24 cytokines), blood pressure, gingival bleeding on probing (BOP), probing pocket depths (PPD), and clinical attachment levels (CAL) were studied. Results: Statistical analyses of baseline study data failed to demonstrate study group differences. The mean weight reduction was greater in the OBND group (4.1 kg) versus the control group (1.3 kg) (p < 0.01). The reduction in BMI was 1.4 kg/m2 in OBND (p < 0.001) and 0.5 kg/m2 in the control group, respectively (p < 0.01). Diastolic and systolic blood pressure reductions were greater in the OBND group than in the control group (p < 0.01). Periodontal study parameters (BOP % scores) and (PPD values) decreased (p < 0.001) overall with no between group differences. The OBND resulted in reduction of serum levels of IFNγ, Eotaxin IL-9, IP10,IL17a, MCP-1,m and PDFBB compared to the control diet. Conclusions: A strict T2D- diet provides an association between reduction in serum HbA1c and BOP scores. Serum levels decreases in IFNγ, Eotaxin IL-9, IP-10, IL17a. MCP-1, and PDFBB were only found in the test group.
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| 5. |
- Wang, Bowen, et al.
(författare)
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Pharmacological and mechanical properties of isolated pig coronary veins
- 2023
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Ingår i: Frontiers in Physiology. - 1664-042X. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Recent successful cardiac transplantation from pig to non-human primates and the first pig-to-human transplantation has put the focus on the properties of the pig heart. In contrast to the coronary arteries, the coronary veins are less well characterized and the aim was to examine the mechanical and pharmacological properties of coronary veins in comparison to the arteries. Vessel segments from the left anterior descending coronary artery (LAD) and the concomitant vein were isolated from pig hearts in cardioplegia and examined in vitro. The wall thickness, active tension and active stress at optimal circumference were lower in coronary veins, reflecting the lower intravascular pressure in vivo. Reverse transcription polymerase chain reaction (RT-PCR) analysis of myosin isoforms showed that the vein could be characterized as having a slower smooth muscle phenotype compared to the artery. Both vessel types contracted in response to the thromboxane agonist U46619 with EC50 values of about 20 nM. The artery contracted in response to acetylcholine. Precontracted arteries relaxed in noradrenaline and substance P. In contrast, the veins relaxed in acetylcholine, contracted in noradrenaline and were unresponsive to substance P. In conclusion, these results demonstrate significant differences between the coronary artery and vein in the smooth muscle properties and in the responses to sympathetic and parasympathetic stimuli.
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