Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intracellular Ca2+-release channels on the sarcoplasmic reticulum of striated muscle [ryanodine receptors (RyRs)] and on the endoplasmic reticulum of almost all types of cells [inositol 1,4,5-trisphosphate receptors (IP3Rs)] comprise a unique family of molecules that are structurally and functionally distinct from all other known ion channels. These channels play crucial roles in Ca2+-mediated signaling that triggers excitation-contraction coupling, T-lymphocyte activation, fertilization, and many other cellular functions. Three forms of RyR have been identified: RyR1, expressed predominantly in skeletal muscle; RyR2, expressed predominantly in cardiac muscle; and RyR3, expressed in specialized muscles and nonmuscle tissues including the brain. RyR channels are tetramers composed of four subunits each with a molecular mass of approximately 560,000 Da. The tetrameric structures of RyR1 and RyR2 are stabilized by a channel-associated protein known as the FK506 binding protein (FKBP). FKBP is the cytosolic receptor for the immunosuppressant drugs FK506 and rapamycin that inhibit the prolyl isomerase activity of FKBP and can dissociate FKBP from RyRs. Rapamycin and FK506 increase the sensitivity of RyRs to agonists such as caffeine and could be a cause of cardiac dysfunction associated with high-dose immunosuppressant therapy by promoting leakage of Ca2+ from the sarcoplasmic reticulum. The role of prolyl isomerase activity of FKBP in regulating RyR function remains uncertain, and several models have been proposed that could explain how the channel is modulated by its association with FKBP. Three forms of IP3Rs (types 1, 2 and 3) have been characterized by cDNA cloning. Most cells have at least one form of IP3R, and many express all three types. Like RyRs, the IP3R channels are tetramers composed of four subunits (approximately 300,000 Da each). IP3R1 function is regulated by at least two major cellular signaling pathways: the second messenger IP3 activates the channel, and phosphorylation by nonreceptor protein tyrosine kinases (e.g., Fyn) increase its open probability. During end-stage human heart failure, RyR2 mRNA and protein are downregulated, whereas IP3R1 is upregulated, suggesting that altered Ca2+-release channel levels may contribute to defects in Ca2+ homeostasis. Cells that are deficient in IP3R1 exhibit defective T cell-receptor signaling and thus cannot be activated by T cell-receptor stimulation. IP3R1-deficient cells are also resistant to induced apoptosis. Thus RyRs and IP3Rs play critical roles in fundamental and diverse signaling phenomena that include excitation-contraction coupling, T-cell activation, and programmed cell death.
 ...
PMID:Intracellular calcium-release channels: regulators of cell life and death. 912 14

Since its beginning in 1967 heart transplantations have become in 80s of the 20th century a routine treatment method of an advanced heart failure. In spite of the successes in transplantations a range of possible topics and research goals still has to be disclosed to improve quality of life and survival of patients. New horizons in heart transplantations can be summarised in following points: 1 Search of new more efficient immunosuppressives with less adverse effects. Classically a combination of Cyclosporin, Azathioprin, and corticoids have been used. Mycophenolate mofetil starts to be used in treatment instead of Azathioprin, Tacrolimus has been introduced as a drug for resistant rejections and also Rapamycin or Baziliximab are planned to be used in future. Use of Rapamycin seems desirable in patients suffering from nephropathy because it makes possible to lower doses of Cyclosporin or Tacrolimus or to stop taking them. 2 Diagnostics of rejection episodes without endomyocardial biopsy. From noninvasive methods echocardiography methods are looked for--tissue doppler imaging, densitometry, contrast echocardiography, strain and strain rate or assessing levels of some of the humoral agents: interleukin, cerebral natriuretic peptide or troponin T or direct assessment of donor DNA release in receptor's blood. 3 Earlier diagnostics of vasculopathy (here intravascular ultrasound is possible to use), particularly its pharmacology prevention. Statin treatment has been preventively introduced. 4 Xenotransplantation as a possible way of a heart replacement with an animal heart. Progresses in gene engineering lead to a development of transgenic animals, particularly pigs, with human proteins inserted in their genome and regulating activation of immune system. This way hyperacute rejection could be prevented. A range of unclear questions still remains in this area, particularly ethical ones and a risk of animal diseases transfer onto a human together with transplanted tissue. 5 Transplantation of cells from skeletal muscles (myoblasts) or marrow stem cells. 6 Development of apparatuses able to substitute heart function--total artificial heart. However, a range of questions is still unanswered in this area: a suitable material or source for long-term operation is needed to be found. Heart transplantation has become in last two decades a well-established treatment method of a serious heart failure. In spite of numerous difficulties it extends life of patients and improves its quality. Future will show whether we are able to replace it with other procedures.
 ...
PMID:[New horizons in heart transplantation]. 1565 Nov 55

Two patients with end-stage heart failure and advanced renal dysfunction (under chronic dialysis therapy) underwent heart transplantation. In order to avoid further renal impairment, a calcineurine inhibitor-free immunosuppression regimen based on the sirolimus was used. Although temporary perioperative support with hemofiltration and dialysis was needed, both patients eventually regained a reasonable renal function with no episodes of clinical rejection and normal cardiac function at 13 and 11 months, respectively, after transplantation. Sirolimus-based immunosuppression might be an interesting alternative to calcineurine inhibitors in the management of patients with significant renal impairment.
 ...
PMID:Sirolimus in de novo heart transplant recipients with severe renal impairment. 1644 75

Sirolimus-induced interstitial pneumonitis (SIP) has been reported mainly in renal transplant recipients. However, it has recently been reported with increasing frequency in heart transplantation (HT) patients switched from calcineurin inhibitors (CNIs) to sirolimus. We reviewed the medical records of 30 patients who were treated with sirolimus. Twenty-seven patients were switched from a CNI, 2 patients were initially treated with sirolimus and in 1 patient sirolimus was used to treat a persistent cellular acute rejection. Three patients developed SIP. Symptoms included dry cough, shortness of breath and hypoxemia. High-resolution computed tomography (HRCT) scans showed patchy pulmonary consolidation in a peribronchial distribution or diffuse interstitial pulmonary infiltrates. Before onset of SIP, 2 patients had previous heart failure. Sirolimus discontinuation resulted in a complete resolution of symptoms. SIP is a common and severe adverse event (10%) in HT recipients treated with sirolimus. Drug discontinuation can dramatically improve clinical status. Previous lung injury may play a role in SIP pathogenesis.
 ...
PMID:Sirolimus-associated interstitial pneumonitis in 3 heart transplant recipients. 1696 83

Sirolimus-eluting stents (SESs) and paclitaxel-eluting stents (PESs) significantly decrease the need for repeat interventions compared with bare metal stents. Comparative outcome data from randomized, controlled, head-to-head trials using these systems in a selected group of patients and lesions are conflicting; therefore, we compared clinical outcomes of unselected patients who underwent contemporary percutaneous coronary intervention with SES or PES implantation. In the REWARDS registry, 1-year clinical outcomes of 1,925 patients who received SESs were compared with 844 patients who received PESs. Outcomes at 30 days and 6 months were similar between groups, with a trend toward higher rates of stent thrombosis in the SES group compared with the PES group. Stent thrombosis rate at 12 months was significantly higher in the SES than in the PES group, with cumulative stent thrombosis rates of 1.9% in the SES group and 0.8% in the PES group (p = 0.034). However, overall rates of major adverse cardiac events (MACEs) were similar in the 2 groups at 12 months. After adjusting for significant multivariate predictors of MACEs, the hazard ratio at 1 year was 1.06 (95% confidence interval 0.85 to 1.33, p = 0.607) and the major predictors for MACEs were a history of renal failure, diabetes, previous myocardial infarction, cardiogenic shock, class III or IV heart failure, type C lesions, and saphenous vein grafts. In conclusion, use of SESs and PESs in unrestricted, contemporary practice had comparable outcomes in terms of low rates of revascularization and clinical events. Stent thrombosis continues to be a major concern for SESs and PESs.
 ...
PMID:Long-term clinical outcomes and thrombosis rates of sirolimus-eluting versus paclitaxel-eluting stents in an unselected population with coronary artery disease (REWARDS registry). 1759 39

Cardiac transplantation and mechanical circulatory support are possible options for improving survival and quality of life in patients with isolated cardiac disease and end-stage heart failure. Transplantation is limited by donor availability but has a median survival of 10 years. Post-transplant immunosuppression is often transplant center dependent, but a tacrolimus and mycophenolate mofetil-based regimen may be preferred. Sirolimus may reduce the progression rate of transplant vasculopathy. There has been a trend toward continuous-flow left ventricular assist devices because of their increased durability and reduced size. A variety of surgical and percutaneous ventricular assist devices may be used as a bridge to decision on a patient's candidacy for transplantation. Mechanical circulatory support as destination therapy has not been widely implemented because of poor device durability, but this is expected to change with newer devices. Mechanical circulatory support as a bridge to myocardial recovery has been successful only in a few patients.
 ...
PMID:Current status of cardiac transplantation and mechanical circulatory support. 1926 90

Cardiac transplantation remains the best treatment in patients with advanced heart failure with a high risk of death. However, an inadequate supply of donor hearts decreases the likelihood of transplantation for many patients. Ventricular assist devices (VADs) are being increasingly used as a bridge to transplantation in patients who may not survive long enough to receive a heart. This expansion in VAD use has been associated with increasing rates of allosensitization in cardiac transplant candidates. Anti-HLA antibodies can be detected before transplantation using different techniques. Complement-dependent lymphocytotoxicity assays are widely used for measurement of panel-reactive antibody (PRA) and for crossmatch purposes. Newer assays using solid-phase flow techniques feature improved specificity and offer detailed information concerning antibody specificities, which may lead to improvements in donor-recipient matching. Allosensitization prolongs the wait time for transplantation and increases the risk of post-transplantation complications and death; therefore, decreasing anti-HLA antibodies in sensitized transplant candidates is of vital importance. Plasmapheresis, intravenous immunoglobulin, and rituximab have been used to decrease the PRA before transplantation, with varying degrees of success. The most significant post-transplantation complications seen in allosensitized recipients are antibody-mediated rejection (AMR) and cardiac allograft vasculopathy (CAV). Often, AMR manifests with severe allograft dysfunction and hemodynamic compromise. The underlying pathophysiology is not fully understood but appears to involve complement-mediated activation of endothelial cells resulting in ischemic injury. The treatment of AMR in cardiac recipients is largely empirical and includes high-dose corticosteroids, plasmapheresis, intravenous immunoglobulin, and rituximab. Diffuse concentric stenosis of allograft coronary arteries due to intimal expansion is a characteristic of CAV. Its pathophysiology is unclear but may involve chronic complement-mediated endothelial injury. Sirolimus and everolimus can delay the progression of CAV. In some nonsensitized cardiac transplant recipients, the de novo formation of anti-HLA antibodies after transplantation may increase the likelihood of adverse clinical outcomes. Serial post-transplantation PRAs may be advisable in patients at high risk of de novo allosensitization.
 ...
PMID:Management of allosensitized cardiac transplant candidates. 1977 95

Simultaneous heart and kidney transplantation (SHKT) has become an accepted therapeutic option for patients with end-stage heart failure associated with end-stage renal disease. The immunosuppressive therapy is usually based upon a heart transplantation protocol using a calcineurin inhibitor (CNI). Sirolimus (SRL) is a potent nonnephrotoxic immunosuppressant with antiproliferative activity in nonimmune cells. Its use has recently been reported to show less nephrotoxicity among both heart and kidney transplants. However, the data for the SHKT are limited. We retrospectively examined the causes of 5 patients who received combined SRL-CNI immunosuppressive therapy with reduced CNI doses from 2003 to 2009. There was no mortality during follow-up. Two of the 3 patients who received a conversion regimen recovered renal function. One who suffered severe proteinuria after transplantation proceeded to hemodialysis at 3 years after conversion. Both of the patients who received the combined regimen de novo remained stable regarding their renal function. Cardiac function was stable in these patients; there was neither allograft rejection nor allograft coronary vasculopathy. We observed that patients without dyslipidemia or hyperuricemia before SHKT were less likely to develop these disorders under the combined regimen. Early medical intervention after close follow-up of lipid and uric acid values by dose adjustments resulted in a stable status of our patients.
 ...
PMID:Combined sirolimus-calcineurin inhibitor immunosuppressive therapy in simultaneous heart and kidney transplantation: a retrospective analysis of a single hospital's experience. 2043 Feb 8

Renal transplantation is associated with increased incidence of cancer. We reviewed a large series of renal transplant recipients to determine the incidence and outcome of patients with malignant changes located at the head and neck. A total of 1232 renal transplant recipients have been followed at Department of Dialysis University Hospital Centre Zagreb from 1972 to 2009. Demographic data, localization and disease outcome were evaluated in patients who developed cancer. Twenty one patients (1.7%) developed 27 head and neck malignancies. The average time from transplantation to development of cancer was 56.8 months. The mean length of follow-up was 9.4+/-4.8 years. Eighteen malignancies were cutaneous in origin and 9 were noncutaneous. Of cutaneous malignancies, 88.9% were basal cell carcinoma; one patient had Merkell-cell carcinoma and one patient developed squamous cell carcinoma. Six cases of basocellular skin cancer were recorded in one fair-skin patient. Noncutaneous malignancies involved the oral cavity (2 cases of Kaposi's sarcoma and one pharyngeal cancer) and the thyroid gland in 3 patients each. Two patients had post-transplant lymphoproliferative disorder occurring at the head and neck. One patient had brain tumor. Radical surgery, radiation, and/or chemotherapy were necessary in 33.3% of patients. Immunosuppression was reduced in all patients, and 12 patients were switched from the calcineurin-based immunosuppression to sirolimus. They all have stable graft function. None of the patients died from cancer. Immunosuppression was ceased in one patient with Kaposi's sarcoma who returned to dialysis and died 10 years later from heart failure. An increased incidence of cancer occurring in the head and neck was recorded. Careful skin examination and oral examination is mandatory for discovering cancer before dissemination. Sirolimus is safe alternative to calcineurin-based immunosuppression in patients who developed head and neck malignancies.
 ...
PMID:Head and neck malignancies in Croatian renal transplant recipients. 2043 29

An 80-year-old woman was admitted to our emergency department with ongoing dyspnea for 2 weeks. The patient was immediately intubated endotracheally because of the hypoxia with flush pulmonary edema. Electrocardiogram showed ST depression and echocardiogram showed hypokinesis of anterior left ventricular wall with poor systolic function. Also her cardiac enzymes were elevated, emergency coronary angiogram was performed from radial artery because both femoral arteries were not fully palpable. Coronary angiogram showed three vessels disease including chronic total occlusion of right coronary artery and left main bifurcation lesion. Also blood flow of left anterior descending coronary artery was delayed. Acute coronary syndrome was the cause of acute heart failure and revascularization was needed but aortography revealed total occlusion of infrarenal aorta. Patient was relatively hemodynamically stable; we planned treating total occlusion of infrarenal aorta with endovascular therapy to maintain a rout for cardiopulmonary support system. With bi-directional approach from both femoral artery and left brachial artery, occlusion site with heavy calcification was finally passed through by guide wire from retrograde approach. After pull-through technique, self-expanding nitinol stent was implanted after pre dilation with small balloon. Considering her EURO score, supposed perioperative mortality was high, percutaneous coronary intervention was performed. A 7 fr sheath was inserted from right femoral artery and intra-aortic balloon pump was inserted from left femoral artery. Sirolimus-eluting stent was implanted to left circumflex artery and also from ostium of left main to mid left anterior descending coronary artery after using an atherectomy device. After successful revascularization, patient became hemodynamically stable and weaning off the respirator was successful. Reporting case achieved successful revascularization to severe coronary artery disease after endovascular recanalization with infrarenal aortic occlusion.
 ...
PMID:A case achieved successful revascularization to severe ischemic coronary artery disease after endovascular recanalization with infrarenal aortic occlusion. 2262 2


1 2 Next >>