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Philipp Sievers,1 Lorenz Uhlmann,2 Sevil Korkmaz-Icöz,3 Christian Fastner,1 Florian Bea,1 Erwin Blessing,1 Hugo A Katus,1 Michael R Preusch11Department of Internal Medicine III, 2Institute of Medical Biometry and Informatics, 3Department of Cardiac Surgery, University of Heidelberg, Heidelberg, GermanyIntroduction: Besides their blood pressure-lowering effects, olmesartan medoxomil and amlodipine besylate exhibit additional anti-inflammatory mechanisms in atherosclerosic disease. Most of the studies investigating the effects of atherosclerosis focused on early atherosclerotic lesions, whereas lesions in human disease, at the time when medical treatment is started, are already well established. Therefore, we set up a model of advanced atherosclerosis and investigated the effects of olmesartan medoxomil, amlodipine besylate, and the combination of both on atherosclerotic lesion size and lesion composition.Materials and methods: Olmesartan medoxomil (1 mg/kg/day), amlodipine besylate (1.5 mg/kg/day), and the combination of both was added to chow and was fed to apolipoprotein E-deficient (ApoE-/-) mice at 25 weeks of age. Mice were sacrificed after 25 weeks of drug administration and perfused with formalin. Innominate arteries were dissected out and paraffin embedded. Serial sections were generated, and lesion sizes and their composition – such as minimal thickness of the fibrous cap, size of the necrotic core, and presence of calcification – were analyzed. Electrophoretic mobility shift assays were used to detect DNA-binding activity of the transcription factor nuclear factor-kappa B (NF-κB) in aortic tissue.Results: Treatment with the combination of olmesartan medoxomil and amlodipine besylate led to a significant reduction in atherosclerotic lesion size in ApoE-/- mice (olmesartan medoxomil/amlodipine besylate: 122,277±6,795 µm2, number [n]=14; versus control: 177,502±10,814 µm2, n=9; P

This article, published in the journal Thoracic & Cardiovascular Surgeon, explores the potential benefits of inhibiting the cysteine protease cathepsin C (CatC) in improving graft function after heart transplantation (HTX) in rats. The study found that the CatC inhibitor BI-9740 decreased the proteolytic activity of neutrophil serine proteases and improved both systolic and diastolic function in the transplanted hearts. Additionally, the inhibitor was associated with a shorter graft re-beating time. These findings suggest that pharmacological inhibition of CatC may be a promising approach to enhance graft function after HTX. [Extracted from the article]

Hearts donated after circulatory death (DCD) are exposed to ischemia, followed by ex-vivo blood perfusion (EVBP). Ischemia and ischemia/reperfusion lead to increased levels of proinflammatory mediators, which can promote contractile dysfunction. Therefore, we investigated the effect of an integrated cytokine adsorber during EVBP of DCD hearts. In a pig model of DCD, the left-ventricular (LV) contractility was either assessed for 60 min with a balloon catheter immediately after procurement (DCD-group), or hearts were maintained by EVBP with (DCD-BCytoS group) or without (DCD-B) an integrated cytokine adsorber (CytoSorb®, Cytosorbents) for 4 h before contractile assessment. In a Control group, no circulatory death was induced (all groups N=8). We measured LV contractility with a balloon catheter. We determined 13 cytokines at the beginning and end of the 4 h of EVBP and performed transcriptomics for LV myocardial samples using gene microarrays (25,470 genes). In DCD-BCytoS, the end-systolic pressure (ESP; Control: 163±9 mmHg/s, DCD: 128±5 mmHg/s, DCD-B: 125±10 mmHg/s, DCD-BCytoS: 172±9 mmHg/s; p<0.05) and maximal slope of pressure increment (dp/dt max ; Control: 2010±39 mmHg/s, DCD: 1219±164 mmHg/s, DCD-B: 964±163 mmHg/s, DCD-BCytoS: 1794±205 mmHg/s; p<0.05) was significantly higher compared to DCD-B and DCD. Lactate decreased stronger in DCD-BCytoS compared to DCD-B after 4 h of perfusion (45±5% vs. 69±9% of initial values, p=0.036). After 4 h of machine perfusion, the concentrations of INF-γ and IL-1α were higher, and IL-1β, -1ra, and -8 were lower in DCD-BPCytoS. In DCD-B, 14 genes were up-, and 12 were downregulated; in DCD-BCytoS, 151 were up-, and 257 were downregulated, compared to DCD. In DCD-BCytoS compared to DCD-B, 43 genes were upregulated, involved in anti-apoptotic pathway, VEGFR2-mediated cell proliferation and reduction of purinergic receptor(PR)-mediated vasoconstriction, and 70 genes were downregulated, involved in inflammation, coagulation, response to endoplasmatic reticulum stress and PR-mediated vasoconstriction. Cytokine adsorption during EVBP of porcine DCD hearts improves LV contractility, alters the perfusates´ cytokine profile, and mediates the upregulation of protective and downregulation of potentially detrimental pathways. [ABSTRACT FROM AUTHOR]

Del Nido cardioplegia (dNC) is a 1:4 formula of blood:crystalloid and contains erythrocytes as oxygen carriers. Hearts donated after circulatory death (DCD) are maintained by ex-vivo machine perfusion (EVMP) with blood. Nevertheless, we already showed in a porcine model that EVMP with crystalloid histidine-tryptophane-ketoglutarate-N (HTK-N) is superior to blood to preserve left-ventricular (LV) contractility. However, the effect of EVMP with dNC on contractility and myocardial microcirculation of DCD hearts is unkown. In a pig model of DCD, hearts were harvested and maintained for 4 h by EVMP with hypothermic, oxygenated HTK-N (DCD-HTK-N) or dNC (DCD-dNC) followed by reperfusion with blood for 2 h including assessment of LV contractility and myocardial microvascular flow with a Laser-Doppler-Flow (LDF) probe. In a DCD group, hearts underwent reperfusion including functional evaluation immediately after procurement. In a Control group, no circulatory death was induced (all groups N=8). We performed transcriptomics for LV myocardial samples using gene microarrays (25,470 genes). In DCD-HTK-N, the end-systolic pressure (ESP; Control: 188±10 mmHg, DCD: 136±9 mmHg, DCD-HTK-N: 165±7 mmHg/s, DCD-dNC: 120±5 mmHg/s; p<0.05), maximal slope of pressure increment (dp/dt max ; Ctrl: 1925±203 mmHg/s, DCD: 1196±257 mmHg/s, DCD-HTK-N: 2291±261 mmHg/s, DCD-dNC: 943±88 mmHg/s; p<0.05) and of pressure decrement (dp/dt min ; Ctrl: -1060±94 mmHg/s, DCD: -730±78 mmHg/s, DCD-HTK-N: -1037±168 mmHg/s, DCD-dNC: -571±51 mmHg/s) was superior in DCD-HTK-N. Relative LDP was higher in DCD-HTK-N compared to DCD-dNC (1.46±0.1 vs. 1.27±0.9). In DCD-HTK-N, 52 genes were up-, and 188 were downregulated; in DCD-dNC, 6 were up-, and 109 were downregulated, both compared to DCD. In DCD-dNC compared to DCD-HTK-N, 16 genes were up- (involved in platelet adhesion and arteriosclerosis), and 25 genes were downregulated (involved in TNFR1-induced proapoptotic and NFkB signaling). In EVMP of porcine DCD hearts with hypothermic preservation solutions, compared to dNC, HTK-N is superior to dNC for preserving the systolic and diastolic function, improving myocardial microcirculation and mediating the upregulation of protective and downregulation of apoptotic pathways. [ABSTRACT FROM AUTHOR]

Coronary artery bypass surgery can result in endothelial dysfunction due to ischemia/reperfusion (IR) injury. Previous studies have demonstrated that DuraGraft helps maintain endothelial integrity of saphenous vein grafts during ischemic conditions. In this study, we investigated the potential of DuraGraft to mitigate endothelial dysfunction in arterial grafts after IR injury using an aortic transplantation model. Lewis rats (n = 7-9/group) were divided in three groups. Aortic arches from the control group were prepared and rings were immediately placed in organ baths, while the aortic arches of IR and IR + DuraGraft rats were preserved in saline or DuraGraft, respectively, for 1 h before being transplanted heterotopically. After 1 h after reperfusion, the grafts were explanted, rings were prepared, and mounted in organ baths. Our results demonstrated that the maximum endothelium-dependent vasorelaxation to acetylcholine was significantly impaired in the IR group compared to the control group, but DuraGraft improved it (control: 89 ± 2%; IR: 24 ± 1%; IR + DuraGraft: 48 ± 1%, p < 0.05). Immunohistochemical analysis revealed decreased intercellular adhesion molecule-1, 4-hydroxy-2-nonenal, caspase-3 and caspase-8 expression, while endothelial cell adhesion molecule-1 immunoreactivity was increased in the IR + DuraGraft grafts compared to the IR-group. DuraGraft mitigates endothelial dysfunction following IR injury in a rat bypass model. Its protective effect may be attributed, at least in part, to its ability to reduce the inflammatory response, oxidative stress, and apoptosis., (© 2024. The Author(s).)

Protection of the coronary arteries during donor heart maintenance is pivotal to improve results and prevent the development of coronary allograft vasculopathy. The effect of hypothermic, oxygenated perfusion (HOP) with the traditional HTK and the novel HTK-N solution on the coronary microvasculature of donation-after-circulatory-death (DCD) hearts is known. However, the effect on the coronary macrovasculature is unknown. Thus, we maintained porcine DCD hearts by HOP with HTK or HTK-N for 4 h, followed by transplantation-equivalent reperfusion with blood for 2 h. Then, we removed the left anterior descending coronary artery (LAD) and compared the endothelial-dependent and -independent vasomotor function of both groups using bradykinin and sodium-nitroprusside (SNP). We also determined the transcriptome of LAD samples using microarrays. The endothelial-dependent relaxation was significantly better after HOP with HTK-N. The endothelial-independent relaxation was comparable between both groups. In total, 257 genes were expressed higher, and 668 genes were expressed lower in the HTK-N group. Upregulated genes/pathways were involved in endothelial and vascular smooth muscle cell preservation and heart development. Downregulated genes were related to ischemia/reperfusion injury, oxidative stress, mitochondrion organization, and immune reaction. The novel HTK-N solution preserves the endothelial function of DCD heart coronary arteries more effectively than traditional HTK.

Donation after circulatory death (DCD) hearts are predominantly maintained by normothermic blood perfusion (NBP). Nevertheless, it was shown that hypothermic crystalloid perfusion (HCP) is superior to blood perfusion to recondition left ventricular (LV) contractility. However, transcriptomic changes in the myocardium and coronary artery in DCD hearts after HCP and NBP have not been investigated yet. In a pig model, DCD hearts were harvested and maintained for 4 h by NBP (DCD-BP group, N = 8) or HCP with oxygenated histidine-tryptophane-ketoglutarate (HTK) solution (DCD-HTK, N = 8) followed by reperfusion with fresh blood for 2 h. In the DCD group ( N = 8), hearts underwent reperfusion immediately after procurement. In the control group ( N = 7), no circulatory death was induced. We performed transcriptomics from LV myocardial and left anterior descending (LAD) samples using microarrays (25,470 genes). We applied the Boruta algorithm for variable selection to identify relevant genes. In the DCD-BP group, compared to DCD, six genes were regulated in the myocardium and 1915 genes were regulated in the LAD. In the DCD-HTK group, 259 genes were downregulated in the myocardium and 27 in the LAD; and 52 genes were upregulated in the myocardium and 765 in the LAD, compared to the DCD group. We identified seven genes of relevance for group identification: ITPRIP , G3BP1 , ARRDC3 , XPO6 , NOP2 , SPTSSA , and IL-6 . NBP resulted in the upregulation of genes involved in mitochondrial calcium accumulation and ROS production, the reduction in microvascular endothelial sprouting, and inflammation. HCP resulted in the downregulation of genes involved in NF-κB- , STAT3- , and SASP -activation and inflammation.

Background: Off-pump coronary artery bypass grafting (OPCAB) is an alternative to on-pump coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). During OPCAB, the temporary use of an intracoronary shunt and inotropic medication or catecholamines should keep the central hemodynamics constant. Nevertheless, the need for conversion to on-pump CABG often occurs unexpectedly, most likely due to circulation instability. Circulation instability can appear first in peripheral body parts; therefore, peripheral microcirculation might serve as a predictor for the upcoming conversion to on-pump CABG. We investigated the impact of coronary artery ligation and shunt insertion during OPCAB on cutaneous microcirculation (cLDP) with Laser Doppler Perfusion Technology and transcutaneous oxygen partial pressure ( tcpO 2 )., Methods: In a pig model of OPCAB, peripheral circulation was evaluated after cLDP (N = 17) and tcpO 2 (N = 6) monitoring. Systolic, diastolic, and mean arterial pressure were also observed to prove the independence of perfusion measurement results from hemodynamic parameters., Results: Ligation time during cLDP and tcpO 2 monitoring were 101 ± 49 s and 83 ± 33 s, respectively. Shunt time was 11 ± 3 min during cLDP and 13 ± 2 min during tcpO 2 measurement. Ligation of the left anterior descending coronary artery (LAD) reduced cLDP significantly to 88 ± 14% ( p = 0.007) and tcpO 2 to 71 ± 25% ( p = 0.038). Inserting a temporary shunt into the LAD significantly improved cLDP ( p = 0.006) and tcpO 2 ( p = 0.015) compared to ligation. cLDP was restored to 99%, and tcpO 2 was restored to 91% of the baseline level before ligation. All hemodynamic parameters remained stable and did not change significantly during OPCAB., Conclusions: Although hemodynamic parameters stayed constant, peripheral microcirculation was influenced markedly during OPCAB. Inserting a temporary shut into the LAD leads to a complete normalization of peripheral microcirculation, regarding evaluation by cLDP and tcpO 2 ., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2024 The Author(s). Published by IMR Press.)