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Biomedical subjects

Jon A Kobashigawa

Publications and source records attributed to Jon A Kobashigawa.

At least 19 recordsLinked to original sources
PubMed2006

Multicenter retrospective analysis of cardiovascular risk factors affecting long-term outcome of de novo cardiac transplant recipients.

BACKGROUND: Previous risk factor studies in cardiac transplant patients have analyzed pre-transplant risk factors as they relate to outcomes. This study is the first in-depth multicenter assessment of ongoing post-transplant risk factors in heart transplant patients and their impact on 5-year outcomes. METHODS: We reviewed 280 heart transplant patients who survived > 1 year for the impact of post-transplant risk factors (hyperlipidemia, hypertension, diabetes, body mass index [BMI] and renal dysfunction: 8 to 18 possible measurements over 5 years) on outcomes, including death, cardiac allograft vasculopathy (CAV) and non-fatal major adverse cardiac events (NF-MACE). RESULTS: Upon multivariate Cox regression analysis, significant findings were high total-cholesterol for NF-MACE (relative risk [RR] = 4.34, confidence interval [CI] 1.35 to 13.98, p = 0.01), presence of diabetes for NF-MACE (RR = 3.96, CI 1.24 to 12.65, p = 0.02) and high serum creatinine for graft death (RR = 1.59, CI 1.35 to 1.87, p < 0.001). No covariates were found to be significant for CAV. Other significant risk factors by univariate Cox regression models with time-dependent covariates included BMI > or = 33 for graft death. CONCLUSIONS: Post-transplant risk factors of hypercholesterolemia and diabetes are associated with NF-MACE, whereas high serum creatinine and BMI > or = 33 are associated with graft death. Risk factor modification, including direct therapy to minimize risk factors, should be considered.

Adult↗
PubMed2006

Similar efficacy and safety of enteric-coated mycophenolate sodium (EC-MPS, myfortic) compared with mycophenolate mofetil (MMF) in de novo heart transplant recipients: results of a 12-month, single-blind, randomized, parallel-group, multicenter study.

BACKGROUND: Enteric-coated mycophenolate sodium (EC-MPS, myfortic) is an advanced formulation that delays the release of mycophenolic acid (MPA). Its efficacy and safety has been proven in several clinical trials in renal transplantation. METHODS: In a single-blind, multicenter trial, a total of 154 de novo heart transplant patients were randomized to either EC-MPS 1,080 mg twice daily or mycophenolate mofetil (MMF) 1,500 mg twice daily. Eligible patients included men or women aged 18 to 65 years, undergoing primary heart transplantation, who were treated with cyclosporine microemulsion and corticosteroids as basic immunosuppression. The primary study objective was to investigate the incidence of biopsy-proven and treated acute rejection, graft loss or death (defined as treatment failure) for EC-MPS vs MMF during the first 6 months of treatment in de novo heart transplant recipients. Secondary objectives included assessment of the overall safety and tolerability of EC-MPS vs MMF in the study population. RESULTS: The primary efficacy variable, treatment failure at 6 months, was similar for both treatments: 52.6% for EC-MPS and 57.9% for MMF (2-sided 95% confidence interval [CI]: -21.0% to 10.4%). At 12 months, treatment failure was 57.7% for EC-MPS and 60.5% for MMF (2-sided 95% CI: -18.4 to 12.7), and death and graft loss rate was 5.1% vs 9.2% for EC-MPS and MMF at 12 months, respectively (2-sided 95% CI: -12.2 to 4.1). The overall safety profile was similar for both groups. Significantly more patients on MMF had two or more study medication dose reductions during the treatment period. CONCLUSIONS: These 6- and 12-month results show that EC-MPS is therapeutically similar to MMF in de novo heart transplant recipients and has a comparable safety profile.

Adolescent↗
PubMed2006

Vascular remodelling after cardiac transplantation: a 3-year serial intravascular ultrasound study.

AIMS: To assess the time-course of intimal hyperplasia and vascular remodelling, and their relative contributions on luminal narrowing in transplant coronary artery disease (TCAD) by a 3-year serial intravascular ultrasound (IVUS) study. METHODS AND RESULTS: Serial IVUS examinations were performed in 90 cardiac transplant recipients at 1.4+/-0.6 months after transplantation and again annually thereafter for 3 years. From 90 arteries, 304 sites were matched from baseline to the third year post-transplant. Based on the change in external elastic membrane (EEM) area +/-10% at 1 year, 304 sites were divided into three groups: sites with no remodelling (52%); early constrictive remodelling (26%); and early compensatory enlargement (22%). Greater intimal growth was seen at 1 year in sites with early compensatory enlargement, whereas there was no change in intimal area in sites with early constrictive remodelling. Over 3 years, the cumulative lumen loss was greater in sites with early constrictive remodelling than in sites with early compensatory enlargement or no remodelling (P<0.001). When luminal narrowing occurred for each annual interval, the contribution from the decrease in EEM area was greater than that due to intimal thickening (P<0.001). CONCLUSION: During the first 3 years post-transplant, the largest intimal growth occurs in the first year, mostly in sites with early compensatory enlargement. The contribution to luminal loss in TCAD is greater from constrictive remodelling than from intimal hyperplasia. The type of remodelling pattern that occurs in transplanted coronary arteries within the first year post-transplant may be a predictor of the progression of luminal narrowing during subsequent years.

Analysis of Variance↗
PubMed2006

Influence of pre-existing donor atherosclerosis on the development of cardiac allograft vasculopathy and outcomes in heart transplant recipients.

OBJECTIVES: This study sought to evaluate the influence of donor lesions on the development of cardiac allograft vasculopathy and outcomes in heart transplant recipients. BACKGROUND: After orthotopic heart transplantation (OHT), coronary artery narrowing occurs as a combination of pre-existing donor lesions and new lesions that develop as a result of cardiac allograft vasculopathy. METHODS: Intravascular ultrasound (IVUS) studies were performed in 301 recipients at 1.3 +/- 0.6 months and again at 12.2 +/- 0.8 months after OHT. Additional IVUS studies were performed in 90 patients at two and three years of follow-up. Sites at baseline with maximum intimal thickness > or =0.5 mm were defined as pre-existing donor lesions. The angiographic diagnosis of transplant coronary artery disease (TCAD) was defined as a new > or =50% diameter narrowing of a major epicardial vessel. RESULTS: Donor lesions were present in 30% of the hearts. By IVUS, sites with donor lesions did not have a greater increase in intimal area compared with sites without donor lesions. Angiographically, the incidence of TCAD up to three years after transplantation was higher in recipients with donor lesions than in recipients without donor lesions (25% vs. 4%, p < 0.001). However, the three-year mortality rate was similar between recipients with or without donor lesions (4.5% vs. 5.2%, p = 1.0). CONCLUSIONS: Pre-existing donor lesions do not act as a nidus for accelerating the progression of intimal hyperplasia. However, patients with donor lesions have a higher incidence of angiographic TCAD. Donor lesions do not affect the long-term survival of patients with OHT up to three years.

Adult↗
PubMed2006

Compensatory enlargement in transplant coronary artery disease: an intravascular ultrasound study.

BACKGROUND: It is unclear to what extent the "Glagov phenomenon" occurs in transplant coronary artery disease (TCAD). The objective of this study was to evaluate the relationship between intimal hyperplasia and compensatory enlargement in TCAD. METHODS: Intravascular ultrasound imaging was performed on 190 cardiac transplant recipients at (1.4 +/- 0.6) months and again (12.1 +/- 0.7) months after cardiac transplantation. Studies 1 year apart were matched at 625 sites. There were 345 coronary artery sites that had an increase in intimal area > 10% from baseline to one year, and this comprised the data set of the present study. RESULTS: At the first year, 91% of coronary artery sites with intimal growth had a total cross-sectional area stenosis < or = 40%, but 38% of the sites showed a decrease of > 10% in lumen area. Receiver operating characteristic curve demonstrated that the change in cross-sectional area stenosis cut-off level at year 1 was 8% with a sensitivity of 75% and a specificity of 82% in predicting lumen loss. At a total cross-sectional area stenosis of 20%, sensitivity was 65% with a specificity of 81% in predicting lumen loss. CONCLUSIONS: In TCAD, vessel enlargement as a compensatory mechanism for plaque growth is generally inadequate. Instead of continued vessel expansion, luminal narrowing develops when there is more than 8% cross-sectional area filled with intimal hyperplasia. In distinction to native coronary artery atherosclerotic disease, the transition point in transplant vasculopathy where the lumen is diminished by increasing intimal growth, occurs at a lower threshold, 20% vs 40% of vessel cross-sectional area.

Adult↗
PubMed2006

Usefulness and safety of percutaneous coronary interventions for cardiac transplant vasculopathy.

Late morbidity and death as a result of progressive coronary vascular obliteration remains a major unsolved problem after orthotopic heart transplantation. Various percutaneous catheter intervention (PCI) methods have been used to treat transplant coronary artery disease (CAD), but few reports have assessed the longitudinal results of these procedures. Of 1,440 cardiac transplant patients at University of California, Los Angeles, Medical Center, treated between 1984 and 2004, 65 patients who had undergone orthotopic heart transplantation underwent PCI on a total of 156 coronary artery lesions because of transplant CAD between July 1993 and August 2004. The procedural success rate was 93%. Angiographic follow-up was available for 42 patients and 101 lesions 9.5 +/- 5.8 months after PCI. The global restenosis rate was 36%. Multivariate analysis was used to assess 49 clinical, angiographic, and immunologic variables per lesion. The use of a cutting balloon increased the risk of restenosis (odds ratio 11.5, p <0.01) and the use of stents decreased the risk of restenosis (odds ratio 0.34, p <0.05) compared with other PCI methods. The restenosis rate with drug-eluting stents was 19%, lower than that with bare metal stents (31%). Of the 65 patients, 20 (31%) died within 1.9 +/- 1.8 years after PCI. The actuarial survival rate was 56% at 5 years after the first PCI. In conclusion, although the restenosis rate after PCI was higher than that in nontransplant patients with CAD, the immediate and long-term results were acceptable in this high-risk population. Despite the intense inflammation associated with transplant CAD, drug-eluting stents appeared to reduce the occurrence of restenosis. Compared with historical controls, PCI may also improve the actuarial survival rate of patients undergoing orthotopic heart transplantation.

Adult↗
PubMed2006

Five-year results of a randomized, single-center study of tacrolimus vs microemulsion cyclosporine in heart transplant patients.

BACKGROUND: Previous multicenter, randomized trials, lacking standardized post-transplant protocols, have compared tacrolimus (Tac) and cyclosporine (CyA, Sandimmune) and demonstrated similar outcomes with some different adverse effects. The microemulsion form of CyA (mCyA, Neoral) has replaced Sandimmune CyA as the more widely utilized CyA formulation. This is the first 5-year follow-up study of a large, single-center trial (n = 67) under a standardized post-transplant protocol comparing Tac and mCyA. METHODS: Sixty-seven heart transplant patients were randomized to Tac (n = 33) or mCyA (n = 34), both in combination with corticosteroids and azathioprine without cytolytic induction. Five-year end-points included survival, Grade > or = 3A or treated rejection, angiographic cardiac allograft vasculopathy (CAV; any lesion > or = 30% stenosis), renal dysfunction (creatinine > or = 2.0 mg/dl), use of two or more anti-hypertensive medications, percent diabetic and lipid levels. RESULTS: Five-year survival, freedom from Grade > or = 3A or any treated rejection and angiographic CAV, mean cholesterol level and percent diabetic were similar between the two groups. The Tac group had a significantly lower 5-year mean triglyceride level (Tac 97 +/- 34 vs mCyA 175 +/- 103 mg/dl, p = 0.011) and average serum creatinine level (Tac 1.2 +/- 0.5 mg/dl vs mCyA 1.5 +/- 0.4 mg/dl, p = 0.044). There was a trend toward fewer patients requiring two or more anti-hypertensive drugs in the Tac group (Tac 33% vs mCyA 59%, p = 0.065). CONCLUSIONS: Tac and mCyA appear to be comparable with regard to 5-year survival, freedom from rejection and CAV. However, compared with mCyA, Tac appears to reduce the adverse effect profile for hypertriglyceridemia and renal dysfunction and the need for hypertensive medications.

Adult↗
PubMed2006

Acute antibody-mediated rejection of cardiac transplants.

Under the direction of the International Society for Heart and Lung Transplantation, a multidisciplinary review of the cardiac biopsy grading system was undertaken in 2004, with task forces examining the areas of histopathology of rejection, clinical issues, and research. An important new area addressed by the Immunopathology Task Force sub-committee was the clinical and diagnostic criteria for antibody-mediated rejection. This article is a companion paper to the revised working formulation for the standardization of nomenclature in the diagnosis of heart rejection and reviews the published literature documenting the serologic and morphologic evidence that antibody-mediated rejection is clinically significant and associated with graft loss, accelerated transplant-associated coronary artery disease, and death. This article also provides a more in-depth analysis of antibody-mediated rejection developed by the Immunopathology Task Force for revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection.

Antibodies↗
PubMed2006

Immunosuppression for heart transplantation: where are we now?

The success of cardiac transplantation is largely attributable to the development of effective immunosuppressive regimens. The introduction of calcineurin inhibitors was pivotal in reducing the frequency of acute rejection and improving early survival. Newer agents, including mycophenolate mofetil (MMF) and proliferation-signal inhibitors, have shown promise in further reducing acute-rejection rates and, notably, reducing the frequency of cardiac allograft vasculopathy, which limits long-term graft survival. The introduction of first-year intravascular ultrasonography results as a surrogate marker for outcome after cardiac transplantation has helped assessment of the efficacy of immunosuppressive medications. Proliferation-signal inhibitors and MMF were shown by this imaging method to reduce cardiac allograft vasculopathy. The combination of these drugs, in tandem with the weaning of patients off calcineurin inhibitors, has been shown to reverse calcineurin-inhibitor-related nephrotoxic effects. A randomized trial that compared three of the more common immunosuppressive regimens suggested that tacrolimus and MMF are associated with a reduction in the frequency of rejection episodes that require treatment and have the fewest adverse effects. Finally, the use of statins has brought added benefit to immunosuppressive regimens by improving outcomes after cardiac transplantation, reportedly because of an immunomodulatory property. Promising newer immunosuppressive agents await clinical trials. This review presents an overview of the emerging data on immunosuppressive therapy for cardiac transplantation.

Dose-Response Relationship, Drug↗
PubMed2006

Should we be doing routine biopsy after heart transplantation in a new era of anti-rejection?

PURPOSE OF REVIEW: The endomyocardial biopsy has defined the diagnosis of rejection in cardiac transplantation and has historically been a vital tool when rejection rates following transplantation were high. Surveillance biopsies have been the cornerstone of post-transplant management, as signs or symptoms of rejection are non-specific. With significant improvements in immunosuppressive therapy, however, the incidence of clinically significant rejection has declined, bringing into question the need for routine surveillance biopsy. This article reviews the current role of the endomyocardial biopsy in the management of patients following cardiac transplantation. RECENT FINDINGS: The endomyocardial biopsy is also limited by sub-optimal interobserver reproducibility, a lack of consensus with regard to treating certain grades of rejection, and often a lack of histological findings in patients with hemodynamic compromise, which frequently responds to anti-rejection therapy. Recent refinements, however, have allowed improved diagnosis of antibody mediated rejection, a relatively recently recognized entity. Moreover, a number of non-invasive modalities have been investigated recently as potential substitutes for the endomyocardial biopsy in detecting rejection. SUMMARY: Despite the development of a variety of non-invasive methods for the detection of rejection, the endomyocardial biopsy will remain important in the management of patients following cardiac transplantation, as non-invasive techniques are associated with low specificity for the diagnosis of rejection. A new standardized classification will likely improve the utility of the biopsy by simplifying interpretation of cellular rejection and importantly allowing recognition of antibody-mediated rejection.

Biopsy↗
PubMed2006

Everolimus: an immunosuppressive agent in transplantation.

Everolimus is a novel immunosuppressive agent related to sirolimus. It is a proliferation signal inhibitor with an improved pharmacokinetic profile and bioavailability compared with sirolimus. Everolimus has been shown to be as effective as mycophenolate mofetil in reducing acute rejection in renal transplantation. In cardiac transplant recipients, it is superior to azathioprine in reducing acute rejection and cardiac allograft vasculopathy. Its use is also associated with a decrease in cytomegalovirus infection. However, coadministration with calcineurin inhibitors requires careful dose adjustment to prevent renal toxicity. Antiproliferative effects of everolimus may abrogate the increased risk of malignancy seen in solid organ transplantation.

Animals↗
PubMed2005

Review of major clinical trials with mycophenolate mofetil in cardiac transplantation.

Over the past 10 years, the addition of mycophenolate mofetil (MMF) to combination immunosuppressive regimens in cardiac transplant patients has resulted in significant outcomes benefits. Randomized trials and other studies have demonstrated that the use of MMF is associated with a decreased risk of rejection and improved survival. This article will provide an overview of these trials, as well as those evaluating MMF in renal-sparing regimens and in pediatric cardiac transplant recipients. In addition, emerging evidence demonstrating that MMF may provide long-term benefits in reducing cardiac allograft vasculopathy and those evaluating the role of MMF therapeutic drug monitoring in cardiac transplant recipients will be discussed.

Adrenal Cortex Hormones↗
PubMed2005

Multicenter intravascular ultrasound validation study among heart transplant recipients: outcomes after five years.

OBJECTIVES: We sought to assess the validity of first-year intravascular ultrasound (IVUS) data as a surrogate marker for long-term outcome after heart transplantation. BACKGROUND: Cardiac allograft vasculopathy (CAV) is a major impediment to long-term graft survival. Intravascular ultrasound is more sensitive than coronary angiography and detects intimal thickening (early CAV) in the coronary arteries of the donor heart. Single-center studies have suggested first-year IVUS results might be a surrogate marker for long-term outcome. METHODS: First-year IVUS results and subsequent five-year clinical follow-up data were reviewed in 125 heart transplant recipients from five institutions. The IVUS tapes (at baseline and one year) were re-analyzed at a core IVUS laboratory. The change in maximal intimal thickness (MIT) from baseline to one year was recorded for several matched sites in the same coronary artery. Patients were classified into two groups: those with >/=0.5 mm in the MIT in any matched site (group 1) and those with MIT <0.5 mm (group 2). RESULTS: Group 1 patients compared with group 2 patients had a higher incidence of death or graft loss (D/GL, 20.8% vs. 5.9%; p = 0.007), had more nonfatal major adverse cardiac events and/or D/GL (45.8% vs. 16.8%; p = 0.003), and had more findings of newly occurring angiographic luminal irregularities (65.2% vs. 32.6%, p = 0.004). CONCLUSIONS: This multicenter study suggests that progression of intimal thickening >/=0.5 mm in the first year after transplantation appears to be a reliable surrogate marker for subsequent mortality, nonfatal major adverse cardiac events, and development of angiographic CAV through five years after heart transplantation.

Adult↗
PubMed2005

Ten-year follow-up of a randomized trial of pravastatin in heart transplant patients.

BACKGROUND: Outcomes from this trial's first year data demonstrated significant benefit in heart transplant patients treated with pravastatin in cholesterol levels, survival, rejection with hemodynamic compromise, the development of cardiac allograft vasculopathy, and decreased natural killer cell cytotoxicity. Other heart transplant studies have shown similar benefit. We now report the 10-year follow-up of this study. METHODS: Ninety-seven heart transplant recipients were randomized to pravastatin (n = 47) or no pravastatin (n = 50) within 2 weeks after surgery both in combination with cyclosporine and corticosteroids. Ten-year outcomes include survival, cholesterol levels, and development of cardiac allograft vasculopathy documented by coronary angiography. RESULTS: Forty-two percent of the control patients crossed over to pravastatin treatment during the second year of the study, and 81% of the control patients were eventually placed on statin therapy by the 10-year follow-up. The control group had subsequent low and comparable cholesterol levels in Years 2 to 10 of the study compared with the patients originally randomized to pravastatin. Intent-to-treat analysis demonstrated that the pravastatin group compared with control had increased 10-year survival (68% vs 48%, p = 0.026). The 10-year freedom from angiographic cardiac allograft vasculopathy and/or death in the pravastatin group was significantly greater compared with the control group (43% vs 20%, p = 0.009). CONCLUSION: The 10-year follow-up of this study suggests that the use of pravastatin in heart transplant patients maintains survival benefit and appears to reduce the development of cardiac allograft vasculopathy.

Adult↗
PubMed2005

The economic implications of noninvasive molecular testing for cardiac allograft rejection.

Endomyocardial biopsy is the mainstay for monitoring cardiac allograft rejection. A noninvasive strategy--peripheral blood gene expression profiling of circulating leukocytes--is an alternative with proven benefits, but unclear economic implications. Financial data were obtained from five cardiac transplant centers. An economic evaluation was conducted to compare the costs of outpatient biopsy with those of a noninvasive approach to monitoring cardiac allograft rejection. Hospital outpatient biopsy costs averaged 3297 US dollars, excluding reimbursement for professional fees. Costs to Medicare and private payers averaged 3581 US dollars and 4140 US dollars, respectively. A noninvasive monitoring test can reduce biopsy utilization. The savings to health care payers in the United States can be conservatively estimated at approximately 12.0 million US dollars annually. Molecular testing using gene expression profiling of peripheral circulating leukocytes is a new technology that offers physicians a noninvasive, less expensive alternative to endomyocardial biopsy for monitoring allograft rejection in cardiac transplant patients.

Biopsy↗