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Biomedical subjects

M H Yacoub

Publications and source records attributed to M H Yacoub.

At least 19 recordsLinked to original sources
PubMed2006

Stimulatory effects of atorvastatin on extracellular nucleotide degradation in human endothelial cells.

Endothelial degradation of extracellular nucleotides is known to be an important mechanism in regulation of thrombosis, inflammation and immune response. It is possible that this pathway is a target for pleiotropic drugs such as atorvastatin. We studied therefore the effect of atorvastatin on extracellular nucleotide degradation in human endothelial cells. Atorvastatin treatment of human umbilical vein endothelial cells (HUVEC) and human microvascular endothelial cells (HMEC-1) resulted in significant increase in ATP breakdown and adenosine formation both if analysed in intact cell studies and as enzyme activity in cell lysates. We conclude that one of the beneficial effects of atorvastatin may include acceleration of extracellular nucleotide breakdown. This will attenuate nucleotide mediated pro-inflammatory effect and stimulate protective mechanisms of adenosine.

5'-Nucleotidase↗
PubMed2006

Differences in activities of the enzymes of nucleotide metabolism and its implications for cardiac xenotransplantation.

Xenotransplantation is one be possible solution for a severe shortage of human organs available for transplantation. However, only a few studies addressed metabolic compatibility of transplanted animal organs. Our aim was to compare activities of adenosine metabolizing enzymes in the heart of different species that are relevant to clinical or experimental xenotransplantation. We noted fundamental differences: ecto-5' nucleotidease (E5' N) activity was 4-fold lower in pig and baboon hearts compared to the human hearts while mouse activity was compatible with human and rat activity was three times higher than human. There also were significant differences in AMP-deaminase (AMPD), adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) activities. We conclude that differences in nucleotide metabolism may contribute to organ dysfunction after xenotransplantation.

5'-Nucleotidase↗
PubMed2006

HPLC/tandem ion trap mass detector methods for determination of inosine monophosphate dehydrogenase (IMPDH) and thiopurine methyltransferase (TPMT).

The efficiency of Mycophenolate mofetil (MMF) and Azathioprine (AZA) as immunosuppressive agents depends on the activity of 2 enzymes, inosine monophosphate dehydrogenase (IMPDH) and thiopurine methyltransferase (TPMT) respectively. We present preliminary evaluation of nonradioactive methods that apply HPLC with ion-trap mass detection to measure the activities of IMPDH in peripheral blood mononuclear cells (PBMC) and TPMT in the erythrocytes (RBC). We found IMPDH activity of 0.9 +/- 0.2 nmol/hour/10(6) PBMC and TPMT activity of 19.9 +/- 4.7 nmol/hour/ml RBC in healthy subjects. These methods, following its further validation, could be useful for monitoring the activity in a clinical and experimental setting.

Azathioprine↗
PubMed2006

Characterization of molecules mediating cell-cell communication in human cardiac valve interstitial cells.

Cell-cell interactions and adhesion determine cellular architectural organization, proliferation, signaling, differentiation, and death. We have identified the molecular components of different cell-cell junctions in human valve interstitial cells (ICs) both in situ and in culture. ICs were isolated, cultured, and phenotyped for cell surface and cytoplasmic markers by flow cytometry and immunocytochemistry. Western blotting was used to identify and quantify the molecular components of these cell-cell junctions in human valve ICs and compared with expression in smooth muscle and fibroblast cell types. N-cadherin and desmoglein were weakly detected on a low percentage of ICs, and the other classical cadherins were not detected. alpha- and beta-catenin, but not gamma-catenin, were expressed at equivalent levels by all valve ICs. Valve ICs did not express connexin-32 and -40; however, connexin-26 and -43 were equally expressed by a low percentage of ICs, demonstrating cell surface and cytoplasmic expression ,and connexin-45 was weakly expressed. The other cell types also expressed N-cadherin, alpha- and beta-catenin, desmoglein and connexin-43. The expression of these junctional molecules was predominantly by valve ICs on the inflow side of the valves. Human valve ICs have the ability to communicate with other valve ICs and mediate cell-cell adhesion via N-cadherin, connexin-26 and -43, and desmoglein. The junctions between valve ICs could support an interconnecting and coordinated cellular unit capable of controlling the functionality of the valve.

Cell Communication↗
PubMed2005

The effect of N-methyl-2-pyridone-5-carboxamide--A nicotinamide catabolite on poly ADP-rybosylation and oxidative stress injury in endothelial cells.

This study evaluated the effect of nicotinamide (NA) and its endogenous metabolite 2PY (N-methyl-2-pyridone-5-carboxamide) on the activity of poly (ADP-ribose) polymerase (PARP) and on peroxynitrite-induced injury in endothelial cells. 2PY and NA inhibited isolated PARP with half-maximal constants of 0.53 mM and 0.025 mM, respectively. Exposure to peroxynitrite caused a decrease of the NAD pool in cultured endothelial cells to below 10% of initial level. Addition of 2PY or NA provided partial protection from peroxynitrite-induced NAD depletion, with NA being more effective. 2PY and NA also provide protection from ATP depletion. We conclude that NA as well as 2PY protect from oxidative stress injury in endothelial cells by inhibition of PARP and protection from NAD depletion. This, in turn, protects energetics, allowing maintaining cellular ATP.

Adenosine Diphosphate Ribose↗
PubMed2005

Purine metabolism in pigs and humans and its implications for xenotransplantation.

We compared concentrations of nucleotide substrates and activities of enzymes of nucleotide metabolism in pig and human blood, heart, and kidney. The most important difference was lower ecto-5-nucleotidase (ESN) activity in both pig hearts and kidney. Furthermore, higher hypoxanthine, inosine, adenine, and uracil, but lower uridine and uric acid concentrations were observed in pig blood as compared to human. A twofold increase in UTP concentration has been observed in pig hearts following 4 h perfusion with human blood. Purine metabolism is an important target for genetic and pharmacological manipulation during xenotransplantations.

5'-Nucleotidase↗
PubMed2005

Prevention of adriamycin induced heart failure by an increase in endogenous adenosine production.

Adenosine (Ado) triggers several protective mechanisms that may attenuate development of heart failure, both locally and systemically. We developed a procedure allowing sustained increase in endogenous Ado production by the combined application of Ado metabolism inhibitors and nucleotide precursors. We found that our procedure attenuate the development of heart failure induced by adriamycin.

Adenosine↗
PubMed2005

Exposure to human blood inactivates swine endothelial ecto-5'-nucleotidase.

Ecto-5'-nucleotidase (E5'N) is an extracellular enzyme forming anti-inflammatory and immunosuppressive adenosine. We evaluated whether confrontation of pig heart and endothelial cells with human blood changes the activity of E5'N. Pig hearts were perfused ex vivo with fresh human blood for 4 h. Pig aortic endothelial cells (PAEC) were incubated in vitro with human plasma for 3 h. Ex vivo perfusion of pig heart with fresh human blood resulted in a decrease in E5'N activity to 62% and 61% of initial in wild-type and transgenic pig hearts, respectively. PAEC activity of E5'N decreased to 71% and 50% of initial after 3 h exposure to heat-inactivated and active complement human plasma, respectively, while it remained constant in controls. Pig heart activity of E5'N decreased following exposure to human blood, which may affect adenosine production and exacerbate hyperacute and vascular rejection.

5'-Nucleotidase↗
PubMed2005

Association of improved cardiac function in donors with C34T mutation of the AMP deaminase 1 gene.

Possession of the C34T mutation in AMP deaminase (AMPD1) gene has been shown to be associated with attenuation of the progression of heart failure and improved survival in ischemic heart disease. In this study, we examined the frequency of the mutation in the heart with good and poor cardiac function and in healthy controls. We found that there was no difference in the frequency of the mutation between the patients with heart failure and healthy controls. However, the frequency of the mutation in the healthy donor hearts was much higher when compared to healthy controls or donors with failing hearts.

AMP Deaminase↗
PubMed2005

Lidoflazine combined with nucleotide precursors increases ATP content and adenosine production in cardiomyocytes.

We have previously identified that the nucleoside transport blocker dipyridamole increases adenosine production but may cause depletion of the nucleotide pool in cardiomyocytes during extended exposure and that this effect was abolished by co-administration of adenine and ribose. The present study aimed to establish whether lidoflazine, a newer generation of nucleoside transport inhibitor with calcium antagonist properties, would cause a similar effect. We conclude that lidoflazine did not affect the nucleotide pool while the combined application of lidoflazine with precursors of nucleotide resynthesis increased ATP concentration and further enhanced adenosine production.

Adenine↗
PubMed2005

Expression of human ecto 5' nucleotidase in pig endothelial cells and its implication for adenosine production and xenotransplantation.

Human endothelial activity of ecto-5'-nucleotidase (E5'N) is several times higher than in pig endothelial cells. This may have implication for xenotransplantation due to the role this enzyme plays in conversion of pro-inflammatory and pro-aggreggatory nucleotides into anti-inflammatory and antiaggregatory adenosine. We have shown in this study that human E5'N can be functionally expressed in pig endothelial cells leading to increased adenosine production from both extracellular AMP and ATP. We suggest that E5'N expression in transgenic pigs for xenotransplantation may help to prolong graft survival.

5'-Nucleotidase↗
PubMed2005

AMPD1 C34T mutation selectively affects AMP-deaminase activity in the human heart.

Possession of the nonsense mutation in AMPD 1 C34T gene has been linked to improved survival in patients with heart failure, possibly by promoting the formation of adenosine. This mutation is known to decrease the activity of AMP-deaminase in skeletal muscle. We have found that the AMPD1 mutation decreases the activity of AMP-deaminase in the heart without changing the activity of any other enzymes of adenine nucleotide metabolism. Protective mechanism of this mutation may be thus induced by local cardiac metabolic changes.

AMP Deaminase↗
PubMed2005

Molecules mediating cell-ECM and cell-cell communication in human heart valves.

The specific phenotype of different tissues depends on the interactions of cells with neighboring cells and the surrounding extracellular matrix, which is mediated by cell adhesion receptors including integrins, immunoglobulin family members, syndecans, and selectins. The aim of this study was to investigate the adhesion profile of native human valve interstitial cells (ICs) in situ and in vitro by analyzing these adhesion receptors. Flow cytometry and immunocytochemistry was used to quantify the expression of the specific receptors on ICs cultured from all human cardiac valves, and immunohistochemistry were used to profile their distribution pattern in valve tissue sections. The valve leaflets and cultured ICs from all valves expressed alpha1, alpha2, alpha3, alpha4, and alpha5 integrins to varying degrees and percentages with very little expression of alpha6 and alphaV. Valve leaflet ICs from all valves, expressed predominantly beta1 integrin but no beta3 or beta4 integrin. Syndecan-1 and Syndecan-4 were not detected. Intercellular adhesion molecule-1 was weakly detected, whereas vascular adhesion molecule-1 was barely detectable and E-selectin was not detected. This study has delineated the identity of some of the integrins synthesized and expressed by human valve ICs and the specificity of adhesion molecules with which the valve ICs interact with the extracellular matrix and mediate intercellular interactions. This pattern of expression of cell surface adhesion molecules may be considered as a basis for a fingerprint on which to base future cell alternatives and would provide useful information for valve tissue engineering.

Cell Adhesion↗
PubMed2004

Clinical recovery from end-stage heart failure using left-ventricular assist device and pharmacological therapy correlates with increased sarcoplasmic reticulum calcium content but not with regression of cellular hypertrophy.

BACKGROUND: Left ventricular assist device (LVAD) treatment is known to lead to structural and functional cellular modifications in the heart. The relevance of these changes for clinical recovery is unknown. METHODS AND RESULTS: We compared properties of cardiomyocytes obtained from tissue taken at explantation of the LVAD in patients with clinical recovery with those obtained from hearts of patients who did not show clinical recovery, thus requiring transplantation. Compared with myocytes taken at implantation, both the recovery and nonrecovery groups showed approximately 50% reduction in cell capacitance, an index of cell size. However, action potential duration shortened, L-type Ca2+ current fast inactivation was more rapid, and sarcoplasmic reticulum Ca2+ content was increased in the recovery compared with the nonrecovery group. CONCLUSIONS: These results show that specific changes in excitation-contraction coupling, and not regression of cellular hypertrophy, are specifically associated with clinical recovery after LVAD and further identify sarcoplasmic reticulum Ca2+ handling as a key functional determinant in patients with heart failure.

Caffeine↗
PubMed2004

Incidence and clinical management of life-threatening left ventricular assist device failure.

BACKGROUND: Mechanical device failure can be life-threatening and is becoming increasingly important as left ventricular assist devices (LVADs) are being used for longer periods as a bridge to transplantation (period lengthening due to donor shortage) or recovery, or as destination therapy. However, its incidence and clinical management have not been widely studied. METHODS: We investigated the incidence and management of major device failure for a total of 102 Thoratec/TCI HeartMate and Thoratec PVAD devices implanted at our institution since 1995. RESULTS: The cumulative probability of device failure was 6%, 12%, 27% and 64% at 6 months, 1 year, 18 months and 2 years, respectively. Major failure occurred in 8 (7.8%) patients. Four patients presented as emergency cases with vented electric (VE) failure, and 3, with failure due to a seized motor, were supported on the pneumatic driver to explantation, transplantation or device change. Another patient had a ruptured pump diaphragm and was maintained for 12 hours, but died of a Type B aortic dissection. Four patients underwent elective device change, including 2 of a VE pump, 1 with inlet valve regurgitation and fractured power cable at 414 days, and 1 with inlet valve regurgitation at 656 days, all of whom underwent transplantation or explantation. One patient with VE failure was maintained on the pneumatic driver, then underwent Thoratec paracorporeal ventricular assist device (PVAD) implantation and was transplanted. One Thoratec PVAD patient developed LVAD thrombus, underwent pump replacement, and was transplanted. A further patient on the implantable pneumatic (IP) HeartMate developed a pneumoperitoneum due to a leak at the junction of the pneumatic driveline, which was repaired by inserting a new driveline, and underwent heart/kidney transplantation. CONCLUSIONS: Life-threatening mechanical device failure is not uncommon and increases with time, but can be managed successfully in most patients. Improvements in design and manufacture should further enhance outcome with LVADs.

Adult↗
PubMed2004

Efficacy and safety of fluvastatin therapy for hypercholesterolemia after heart transplantation: results of a randomised double blind placebo controlled study.

BACKGROUND: Hypercholesterolemia is frequent after heart transplantation. Statins can reduce cholesterol levels but their use in heart transplant patients is complicated by pharmacokinetic interactions with cyclosporin and the risk of serious adverse effects including rhabdomyolysis. Fluvastatin has been used safely to treat hypercholesterolemia in renal transplant patients but there are few data relating to its use after heart transplantation. Therefore, we conducted a randomised blinded placebo controlled trial. METHODS AND RESULTS: Seventy-nine patients, 3 months to 12 years after heart transplantation with a low density lipoprotein (LDL) cholesterol between 3.5 and 8.0 mmol/l were randomly assigned, in a 2:1 ratio, to receive either fluvastatin 40 mg od (n=52) or matching placebo (n=27). Changes in total cholesterol (TC) in the fluvastatin and placebo groups were -17.0% and +4.5%, respectively, (p<0.001); the corresponding changes in LDL were -20.5% and +4.8% (P<0.001) and in triglycerides -14.5% and +7.1% (p=0.012) at the end of the 1-year study period. Withdrawals were more frequent in the fluvastatin group (23% vs. 11% p=0.24). Two deaths occurred during the study (the rate expected from International Society of Heart Lung Transplantation registry) and appeared to be unrelated to the study medication. There were no episodes of rhabdomyolysis or other serious drug-related side effects. CONCLUSIONS: Fluvastatin (40 mg/day) was both an effective and a safe treatment for hypercholesterolemia in patients who had undergone heart transplantation more than 3 months previously.

Anticholesteremic Agents↗
PubMed2004

Cyclosporine in thoracic organ transplantation.

The discovery of cyclosporine proved to be a breakthrough that helped transform the status of both heart and lung transplantation from experimental to established therapeutic procedures. Cyclosporine inhibits the early phase of T-cell activation and thus of the alloimmune response. It proved to be highly effective in prophylaxis against acute rejection but its use has been limited by dose-related renal toxicity. Consequently, it has generally been used in regimens that combine it with other immunosuppressive agents with the aim of preventing acute rejection while minimising toxicity. For many years 'triple therapy' using cyclosporine, azathioprine and corticosteroids was the most commonly used regimen for both heart and lung transplantation. Other agents have now become available that provide more effective prophylaxis against acute rejection than azathioprine; these include, mycophenolate and the TOR inhibitors sirolimus and everolimus. Everolimus has also been shown to inhibit the early phase of cardiac allograft vasculopathy. Unfortunately, the TOR inhibitors also potentiate the nephrotoxicity of cyclosporine. Both mycophenolate and the TOR inhibitors are subject to pharmacokinetic interactions with cyclosporine. We are now entering a new phase of clinical immunosuppression where we need to learn how to best combine the agents that are currently available to provide the safest and most effective immunosuppression for patients undergoing heart or lung transplantation.

Calcineurin Inhibitors↗