J. D. Moriguchi

Bio: J. D. Moriguchi is an academic researcher from Cedars-Sinai Medical Center. The author has contributed to research in topics: Heart transplantation & Transplantation. The author has an hindex of 16, co-authored 49 publications receiving 775 citations.

Pretransplant panel reactive-antibody screens. Are they truly a marker for poor outcome after cardiac transplantation?

Abstract: Background The effect of pretransplant sensitization on outcome after cardiac transplant has been controversial. Sensitization, defined as a positive panel-reactive antibody (PRA) screen in patients awaiting transplant, represents circulating antibodies to a random panel of donor lymphocytes (usually T lymphocytes). The significance of pretransplant circulating antibodies to B lymphocytes has not been reported, and many centers disregard its use. Methods and Results We retrospectively reviewed the pretransplant PRA screens for 311 patients who underwent cardiac transplant at our institution. The PRA screen was performed by use of the lymphocytotoxic technique treated with dithiothreitol to remove IgM autoantibodies. Patients with PRA ≥11% against T or B lymphocytes had significantly lower 3-year survival (T lymphocytes, 39% ; B lymphocytes, 56%) than those patients with PRA=0% and PRA=1 % to 10% (T lymphocytes, 76% and 78% ; B lymphocytes, 78% and 74%, respectively) (P<.001). For this high-risk group, the rejection episode tended to occur earlier than in those patients with PRA=0% and PRA= 1 % to 10% (T lymphocytes, 2.3 versus 4.0 and 3.8 months ; B lymphocytes, 2.1 versus 4.1 and 3.4 months, respectively), and there were more clinically severe rejections that required OKT3 therapy. Conclusions Cardiac transplant patients with pretransplant T- and/or B-lymphocyte PRA ≥11% despite negative donor-specific crossmatch at the time of transplant appear to have earlier and more severe rejection with significantly lower survival after transplant surgery. Modification of immunosuppression in these high-risk patients may be warranted.

Low-dose lovastatin safely lowers cholesterol after cardiac transplantation.

Abstract: Hypercholesterolemia occurs in many cardiac transplant patients and may aggravate graft coronary arteriopathy as well as contributing to peripheral vascular disease. Lovastatin, which inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase, in doses of 40-80 mg/day effectively lowers cholesterol in the general cardiac population but has been associated with rhabdomyolysis in cardiac transplant recipients. To determine whether lower doses of lovastatin would be effective and safe for lowering cholesterol after cardiac transplantation, 44 patients with blood cholesterol greater than 200 mg/dl at least 6 months after cardiac transplantation received 10-20 mg lovastatin daily. In addition, lovastatin enzyme inhibitor level was assayed in six patients to determine whether metabolism of the drug was abnormal. Lovastatin decreased total cholesterol by 28% from 282 +/- 54 to 208 +/- 62 mg/dl (p less than 0.005), primarily because of reduction in the low-density lipoprotein fractions, and was well-tolerated without any symptoms or abnormal creatine phosphokinase levels in 43 of 44 patients. One patient developed rhabdomyolysis and reversible renal failure when lovastatin was increased to 40 mg daily. Enzyme inhibitor levels in the six transplant patients were 4.2-7.8 times higher than those measured in normal volunteers. Low-dose lovastatin effectively lowers cholesterol in patients after transplantation, but metabolism is altered, perhaps by cyclosporine. Monitoring of enzyme inhibitor levels may be required to allow safe administration of this drug to cardiac transplant recipients.

Outcomes of patients undergoing transplantation with older donor hearts.

Abstract: Background : The limited number of donor hearts relative to the number of waiting recipients is the major determinate of a growing inequity. Although a number of potential options are being vigorously pursued, the most effective immediate solution is to expand acceptance criteria for donor age and medical condition. This report is a review of our early and late results with the use of older donors, including simultaneously bypassed donor hearts. Methods : Between April 1987 and September 1994, 52 patients received older donor hearts (older than 45 years) with a mean donor age of 51 years. Ten patients in this group received hearts simultaneously bypassed with from 1 to 4 grafts per patient. Donor and recipient age, diagnosis, and HLA match were compared between the older donor group and a contemporaneous younger (younger than 45) donor group (N = 324). Also compared was actuarial survival at up to 5 years of follow-up in addition to graft function, bypass graft patency, infection and rejection incidence at 1 year, and the prevalence of transplant-associated coronary artery disease in the two groups. Echocardiography, coronary angiography, and intravascular coronary ultrasonography were used for this assessment. Results : One-year actuarial survival was 84% for the older donor group, which included 19 status 1 patients (survival 76%) and 23 status II patients (survival 90%). In the bypassed donor subgroup there was a 60% 1-year actuarial survival with 5 status 1 patients (survival 80%) and 5 status II patients (survival 40%). At 1 year, left ventricular function and the incidence of infection and rejection were equal between these two donor groups. Five-year actuarial survivals were the same between the overall older and younger donor groups. Finally, the development of transplant-associated coronary disease was similar in both groups up to 5 years after transplantation. Conclusions : This initial review of heart transplantation with older donor hearts, including bypassed hearts, demonstrates similar early and late survival outcomes as compared with those of a contemporaneous younger donor group. Significantly, there appears to be no difference in the development of transplant-associated coronary artery disease during the follow-up period. The older donor represents a potential immediate increase in the number of suitable hearts for transplantation. Bypassed donor hearts represent a small but potentially significant subgroup that may be safely and effectively used when appropriately matched to the recipient by age and medical condition. Greater experience, particularly with this bypassed group, will help determine optimal donor-to-recipient matching for the future.

University of Wisconsin solution versus Stanford cardioplegic solution and the development of cardiac allograft vasculopathy.

Abstract: Background : University of Wisconsin (intracellular) solution has been shown to offer some distinct benefits of myocardial preservation over Stanford (extracellular) solution, including a more rapid functional recovery, improved adenosine triphosphate preservation, and a tendency for less postoperative inotropic agents. However intracellular solutions with high potassium content have been reported to cause a functional if not structural endothelial injury in laboratory experiments. Methods : Because of this information we retrospectively reviewed our follow-up angiographic data for the development of cardiac allograft vasculopathy in a consecutive series of 195 heart transplant recipients. These patients were treated in identical fashion, with the same immunosuppression regimen, except for the type of cardioplegia used - Stanford solution (group I n = 95) and University of Wisconsin solution (group II n = 100). Results : With a mean follow-up of 24 months after transplantation, a significant difference was seen in the development of cardiac allograft vasculopathy in group II (22%) versus group I (14%, p < 0.03). Although significant differences were observed with univariate analysis with respect to donor age and ischemic time favoring group I and with multivariate statistical analysis with respect to overall rejections favoring group II, the only significant variable for the difference in the development of allograft vasculopathy was University of Wisconsin cardioplegic solution (p < 0.003). A subgroup of 30 patients previously randomized for a functional study comparing the two cardioplegic agents showed a tendency for statistical significance with a freedom from allograft vasculopathy of 93% in group I, as compared with 83% in group II, after 13 months follow-up (p = 0.09). The overall probability of being free of vasculopathy at 24 months was 86% for group I and 70% for group II. Conclusions : The data support the conclusion that University of Wisconsin intracellular solution is associated with an increased incidence of vasculopathy versus Stanford solution and warrants investigation for modification of this preservation agent in heart transplantation.

The alternate recipient list for heart transplantation: does it work?

Abstract: Background One quarter of patients awaiting heart transplantation die while on the waiting list. This is largely due to the shortage of donor organs. The alternate recipient list was created to establish a means by which patients who would otherwise be turned down for heart transplantation solely because of age over 65 or a need for a third heart transplantation can receive organs considered marginal that may otherwise be wasted. The hope is that these patients may achieve improved survival with these substandard hearts than they would achieve with medical therapy alone. Methods Twenty-two patients ages 47 to 71 years (mean 66.7 years) were listed on the alternate recipient list at the University of California at Los Angeles Medical Center from 1991 to 1996. Seventeen patients underwent heart transplantation from the alternate waiting list. The outcome of this group was compared with the outcome of a contemporaneous group of 266 patients ages 18 to 66 years (mean age 52.1 years) from the standard heart transplantation waiting list. Results The early mortality rate for the patients in the alternate group was 11.8% (2/ 17). Actuarial survival from time of orthotopic heart transplantation at 6 months and 1 year was the same 74.5% at a mean follow-up was 13.4 months. In comparison, the early mortality rate for the patients on the standard list was 5.6% (15/266), and actuarial survival at 6 months and 1 year was 86.8% and 83.1%, respectively (mean follow-up was 30 months). There was no significant difference in early mortality rate or actuarial survival between the two groups. Conclusion The alternate recipient list for heart transplantation is a valid and ethical option for patients who would otherwise be denied heart transplantation. It provides these patients with similar early and medium-term outcomes in comparison to patients on the standard list, and organs that may otherwise be wasted are used.

The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients

Abstract: Institutional Affiliations Chair Costanzo MR: Midwest Heart Foundation, Lombard Illinois, USA Task Force 1 Dipchand A: Hospital for Sick Children, Toronto Ontario, Canada; Starling R: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Anderson A: University of Chicago, Chicago, Illinois, USA; Chan M: University of Alberta, Edmonton, Alberta, Canada; Desai S: Inova Fairfax Hospital, Fairfax, Virginia, USA; Fedson S: University of Chicago, Chicago, Illinois, USA; Fisher P: Ochsner Clinic, New Orleans, Louisiana, USA; Gonzales-Stawinski G: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Martinelli L: Ospedale Niguarda, Milano, Italy; McGiffin D: University of Alabama, Birmingham, Alabama, USA; Parisi F: Ospedale Pediatrico Bambino Gesu, Rome, Italy; Smith J: Freeman Hospital, Newcastle upon Tyne, UK Task Force 2 Taylor D: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Meiser B: University of Munich/Grosshaden, Munich, Germany; Baran D: Newark Beth Israel Medical Center, Newark, New Jersey, USA; Carboni M: Duke University Medical Center, Durham, North Carolina, USA; Dengler T: University of Hidelberg, Heidelberg, Germany; Feldman D: Minneapolis Heart Institute, Minneapolis, Minnesota, USA; Frigerio M: Ospedale Niguarda, Milano, Italy; Kfoury A: Intermountain Medical Center, Murray, Utah, USA; Kim D: University of Alberta, Edmonton, Alberta, Canada; Kobashigawa J: Cedar-Sinai Heart Institute, Los Angeles, California, USA; Shullo M: University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Stehlik J: University of Utah, Salt Lake City, Utah, USA; Teuteberg J: University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Uber P: University of Maryland, Baltimore, Maryland, USA; Zuckermann A: University of Vienna, Vienna, Austria. Task Force 3 Hunt S: Stanford University, Palo Alto, California, USA; Burch M: Great Ormond Street Hospital, London, UK; Bhat G: Advocate Christ Medical Center, Oak Lawn, Illinois, USA; Canter C: St. Louis Children Hospital, St. Louis, Missouri, USA; Chinnock R: Loma Linda University Children's Hospital, Loma Linda, California, USA; Crespo-Leiro M: Hospital Universitario A Coruna, La Coruna, Spain; Delgado R: Texas Heart Institute, Houston, Texas, USA; Dobbels F: Katholieke Universiteit Leuven, Leuven, Belgium; Grady K: Northwestern University, Chicago, Illlinois, USA; Kao W: University of Wisconsin, Madison Wisconsin, USA; Lamour J: Montefiore Medical Center, New York, New York, USA; Parry G: Freeman Hospital, Newcastle upon Tyne, UK; Patel J: Cedar-Sinai Heart Institute, Los Angeles, California, USA; Pini D: Istituto Clinico Humanitas, Rozzano, Italy; Pinney S: Mount Sinai Medical Center, New York, New York, USA; Towbin J: Cincinnati Children's Hospital, Cincinnati, Ohio, USA; Wolfel G: University of Colorado, Denver, Colorado, USA Independent Reviewers Delgado D: University of Toronto, Toronto, Ontario, Canada; Eisen H: Drexler University College of Medicine, Philadelphia, Pennsylvania, USA; Goldberg L: University of Pennsylvania, Philadelphia, Pennsylvania, USA; Hosenpud J: Mayo Clinic, Jacksonville, Florida, USA; Johnson M: University of Wisconsin, Madison, Wisconsin, USA; Keogh A: St Vincent Hospital, Sidney, New South Wales, Australia; Lewis C: Papworth Hospital Cambridge, UK; O'Connell J: St. Joseph Hospital, Atlanta, Georgia, USA; Rogers J: Duke University Medical Center, Durham, North Carolina, USA; Ross H: University of Toronto, Toronto, Ontario, Canada; Russell S: Johns Hopkins Hospital, Baltimore, Maryland, USA; Vanhaecke J: University Hospital Gasthuisberg, Leuven, Belgium.

The 2013 International Society for Heart and Lung Transplantation Guidelines for mechanical circulatory support: executive summary.

Abstract: Institutional Affiliations Co-chairs Feldman D: Minneapolis Heart Institute, Minneapolis, Minnesota, Georgia Institute of Technology and Morehouse School of Medicine; Pamboukian SV: University of Alabama at Birmingham, Birmingham, Alabama; Teuteberg JJ: University of Pittsburgh, Pittsburgh, Pennsylvania Task force chairs Birks E: University of Louisville, Louisville, Kentucky; Lietz K: Loyola University, Chicago, Maywood, Illinois; Moore SA: Massachusetts General Hospital, Boston, Massachusetts; Morgan JA: Henry Ford Hospital, Detroit, Michigan Contributing writers Arabia F: Mayo Clinic Arizona, Phoenix, Arizona; Bauman ME: University of Alberta, Alberta, Canada; Buchholz HW: University of Alberta, Stollery Children’s Hospital and Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada; Deng M: University of California at Los Angeles, Los Angeles, California; Dickstein ML: Columbia University, New York, New York; El-Banayosy A: Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania; Elliot T: Inova Fairfax, Falls Church, Virginia; Goldstein DJ: Montefiore Medical Center, New York, New York; Grady KL: Northwestern University, Chicago, Illinois; Jones K: Alfred Hospital, Melbourne, Australia; Hryniewicz K: Minneapolis Heart Institute, Minneapolis, Minnesota; John R: University of Minnesota, Minneapolis, Minnesota; Kaan A: St. Paul’s Hospital, Vancouver, British Columbia, Canada; Kusne S: Mayo Clinic Arizona, Phoenix, Arizona; Loebe M: Methodist Hospital, Houston, Texas; Massicotte P: University of Alberta, Stollery Children’s Hospital, Edmonton, Alberta, Canada; Moazami N: Minneapolis Heart Institute, Minneapolis, Minnesota; Mohacsi P: University Hospital, Bern, Switzerland; Mooney M: Sentara Norfolk, Virginia Beach, Virginia; Nelson T: Mayo Clinic Arizona, Phoenix, Arizona; Pagani F: University of Michigan, Ann Arbor, Michigan; Perry W: Integris Baptist Health Care, Oklahoma City, Oklahoma; Potapov EV: Deutsches Herzzentrum Berlin, Berlin, Germany; Rame JE: University of Pennsylvania, Philadelphia, Pennsylvania; Russell SD: Johns Hopkins, Baltimore, Maryland; Sorensen EN: University of Maryland, Baltimore, Maryland; Sun B: Minneapolis Heart Institute, Minneapolis, Minnesota; Strueber M: Hannover Medical School, Hanover, Germany Independent reviewers Mangi AA: Yale University School of Medicine, New Haven, Connecticut; Petty MG: University of Minnesota Medical Center, Fairview, Minneapolis, Minnesota; Rogers J: Duke University Medical Center, Durham, North Carolina

Clinical pharmacokinetics of atorvastatin.

Abstract: Hypercholesterolaemia is a risk factor for the development of atherosclerotic disease. Atorvastatin lowers plasma low-density lipoprotein (LDL) cholesterol levels by inhibition of HMG-CoA reductase. The mean dose-response relationship has been shown to be log-linear for atorvastatin, but plasma concentrations of atorvastatin acid and its metabolites do not correlate with LDL-cholesterol reduction at a given dose. The clinical dosage range for atorvastatin is 10–80 mg/day, and it is given in the acid form. Atorvastatin acid is highly soluble and permeable, and the drug is completely absorbed after oral administration. However, atorvastatin acid is subject to extensive first-pass metabolism in the gut wall as well as in the liver, as oral bioavailability is 14%. The volume of distribution of atorvastatin acid is 381L, and plasma protein binding exceeds 98%. Atorvastatin acid is extensively metabolised in both the gut and liver by oxidation, lactonisation and glucuronidation, and the metabolites are eliminated by biliary secretion and direct secretion from blood to the intestine. In vitro, atorvastatin acid is a substrate for P-glycoprotein, organic anion-transporting polypeptide (OATP) C and H+-monocarboxylic acid cotransporter. The total plasma clearance of atorvastatin acid is 625 mL/min and the half-life is about 7 hours. The renal route is of minor importance (<1%) for the elimination of atorvastatin acid. In vivo, cytochrome P450 (CYP) 3A4 is responsible for the formation of two active metabolites from the acid and the lactone forms of atorvastatin. Atorvastatin acid and its metabolites undergo glucuronidation mediated by uridinediphosphoglucuronyltransferases 1A1 and 1A3. Atorvastatin can be given either in the morning or in the evening. Food decreases the absorption rate of atorvastatin acid after oral administration, as indicated by decreased peak concentration and increased time to peak concentration. Women appear to have a slightly lower plasma exposure to atorvastatin for a given dose. Atorvastatin is subject to metabolism by CYP3A4 and cellular membrane transport by OATP C and P-glycoprotein, and drug-drug interactions with potent inhibitors of these systems, such as itraconazole, nelfinavir, ritonavir, cyclosporin, fibrates, erythromycin and grapefruit juice, have been demonstrated. An interaction with gemfibrozil seems to be mediated by inhibition of glucuronidation. A few case studies have reported rhabdomyolysis when the pharmacokinetics of atorvastatin have been affected by interacting drugs. Atorvastatin increases the bioavailability of digoxin, most probably by inhibition of P-glycoprotein, but does not affect the pharmacokinetics of ritonavir, nelfinavir or terfenadine.