End-stage Ischemic Heart Research Articles

Identification and characterization of human myocardial phospholipase A2 from transplant recipients suffering from end-stage ischemic heart disease.

Although numerous studies have implicated accelerated phospholipid catabolism during myocardial ischemia as an important contributor to ischemic membrane dysfunction, no information is currently available on the subcellular distribution, physical properties, or kinetic characteristics of human myocardial phospholipase A2. In this report, we demonstrate that the overwhelming majority (98%) of total phospholipase A2 activity in human myocardium (obtained from transplant recipients) is calcium independent, plasmalogen selective, and is distributed between the microsomal (60-70% of total activity) and cytosolic (30-40% of total activity) fractions. Both human myocardial microsomal and cytosolic phospholipase A2 enzymes 1) preferentially hydrolyze plasmalogen molecular species containing arachidonic acid at the sn-2 position, 2) are recalcitrant to chemical inactivation by the indole-reactive agent parabromophenacyl bromide, 3) are irreversibly inhibited by covalent modification of an essential thiol residue by 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB), and 4) are exquisitely sensitive to mechanism-based inhibition by (E)-6-(bromomethylene)tetrahydro-3-(1-naphthalenyl)-2H-pyran-2-one (bromoenol lactone). In sharp contrast, human mitochondrial phospholipase A2 1) accounts for only a diminutive amount of total myocardial phospholipase A2 activity (1-2%), 2) is augmented by calcium ion, 3) exhibits a higher reaction velocity using phosphatidylcholine in comparison with plasmenylcholine substrate, and 4) is not substantially inhibited by either DTNB or bromoenol lactone. Collectively, these results demonstrate that the majority of phospholipase A2 activity in human myocardium is catalyzed by a novel class of calcium-independent plasmalogen-selective phospholipases A2 and underscore the potential importance of this class of enzymes in mediating membrane dysfunction during myocardial infarction in humans.

Morbidity risk factors in human cardiac transplantation. Histoincompatibility and protracted graft ischemia entail high risk of rejection and infection.

Data from the first 103 human heart transplantations performed on 100 recipients (aged 14-62 years) at a single center from November 1983 to January 1990 were analyzed in order to detect morbidity-causing risk factors. Cumulative one- and five-year graft survival was 82% and 68%. Multivariate analysis revealed three independent risk factors for early rejection, viz. HLA-DR and HLA-B mismatches and no prior cardiac surgery. Graft ischemic time exceeding 71 min was an independent risk factor for rejection, especially for moderate or severe events, and for infection. HLA-DR mismatch was an independent risk factor for moderate and severe rejection events and for infections. Finally, patients operated on because of end-stage ischemic heart disease were at significantly higher risk of rejection than those with other cardiac disorders. The study has several implications: Prospective tissue typing for cardiac transplantation and selection of donors may have an impact on graft function: Damage to the graft by prolonged ischemia may be reduced by improved organ preservation.

Heart Transplantation - The Treatment of Choice for Patients With End-Stage Ischaemic Heart Disease

Between December, 1967 and August, 1988, 147 heart transplants (64 orthotopic, 68 heterotopic procedures; 15 heart-and-lung replacements) were performed on 128 patients. In the majority of the recipients, dilated cardiomyopathy or end-stage ischaemic heart disease was diagnosed. From 1985 to the present, 70 transplants (45 orthotopic, 11 heterotopic and 14 heart-lung) took place. Seventeen of these patients (mean age 46.6 years) suffered from end-stage disabling (NYHA IV) coronary artery disease; in each case the angiogram verified severe stenosis or occlusion of the three main coronary artery systems. Their histories revealed a total of 22 previous myocardial infarctions; 8 patients needed a total of 9 surgical revascularization procedures. The left ventricular ejection fraction (LVEF) ranged from 9% to 24% (mean 15.3%). Before transplantation three patients required intraaortic balloon pump (IABP) support. Fourteen of the 17 patients are at present still alive with post operative periods ranging from 8 weeks to 3.5 years (the actuarial 90-days and 1-year-survival rates being respectively 91.7% and 81.5%). Twelve of the patients are in NYHA class I; 2 are in class II. Three late deaths occurred: one from pneumocystic carinii/cytomegalovirus pneumonia, a second from atypical pneumonia and a third from chronic graft rejection. Radionuclide ventricular studies demonstrated postoperative left ventricular ejection fractions ranging from 54%-81% (mean 71%).(ABSTRACT TRUNCATED AT 250 WORDS)

Inotropic Therapy for Cardiac Failure Associated with Acute Myocardial Infarction

COMPARISON OF ACUTE AND CHRONIC FAILURE C ardiac failure is the second most common complication ofmyocardial infarction, occurring in 40-50 percent of patients, usually evident within hours of onset of symptoms, reflecting 20-25 percent involvement of the myocardium. The pathogenesis is quite distinct from that of chronic failure and requires different treatment; however, this is still not fully recognized. In most cases, the failure is transient, the underlying pathology is probably a combination of necrosis and ischemia, with the latter associated with transient ischemic dysfunction. The basic defect is sudden loss of contractile function in association with decreased ventricular compliance. The predominant relevant compensatory effects from increased catecholamines are an increase of the heart rate and myocardial contractility, the latter primarily of the remaining normal myocardium, but to some extent of the ischemic but non-necrotic myocardium. The decreased ventricular compliance results in a higher enddiastolic pressure than normal for a given end-diastolic volume. Since the pressure-volume relationship is on the ascending limb, the cardiac output is very sensitive to any decrease in circulatory volume. For example, a patient in severe failure with acute pulmonary edema from acute myocardial infarction, who has lost 500-700 ml of fluid in his/her lungs at the expense of the vascular volume, may be hypotensive and administration of a diuretic would precipitate a decrease in coronary perfusion. In contradistinction to chronic cardiac failure, such as secondary to valvular, congenital, or end-stage ischemic heart disease, institution of a diuretic would be helpful and well tolerated. The feature of acute ischemic cardiac failure and chronic failure exhibit several important differences as follows: 1) patients are normovolemic or hypovolemic as opposed to hypervolemic; 2) cardiac output is often normal; 3) sodium and water retention, a feature of chronic failure is not present in the initial days of acute cardiac failure, and in patients with inferior infarction, there is a tendency to lose salt and water; 4) cardiomegaly from either dilatation or hypertrophy is absent; 5) catecholamines are markedly elevated; 6) failure is usually transient. This refers primarily to those patients with no previous history of cardiac failure, whereas when superimposed on chronic failure the combined pathophysiology exists. It was assumed for some time that the pathogenesis ofacute failure ofischemic heart disease and of chronic failure was the same, so the traditional regimen of administration of diuretics and digoxin developed for chronic failure was considered appropriate for acute failure. The experience ofthe CCU has highlighted the lack ofhypervolemia and cardiomegaly in acute failure, but habits have changed slowly. Despite the increasing recognition ofthe different pathogenesis, only now are we beginning to change our treatment. There is widespread appreciation of the inappropriateness of therapy with digoxin and the beneficial effect of vasodilators, but the frequent use of diuretics continues despite hypovolemia and the potential for hypotension. The cardiac failure ofacute myocardial infarction is usually left ventricular, with only about 5 percent due to failure ofthe right ventricle. The clinical picture of left ventricular failure is dominated by that of pulmonary congestion, the symptoms of which are often the primary indications for treatment. In patients with mild failure, as evidenced by basal rales and no other symptoms or evidence ofhypoxemia, no specific treatment is recommended other than oxygen and morphine.

Organization, Development and Early Results of a Heart Transplant Program: The Johns Hopkins Hospital Experience

Improved survival and quality of life have resulted in a resurgence in cardiac transplantation and the proliferation of centers contemplating initiation of a transplant program. Organization of such a program requires cooperation among several clinical and non-clinical departments of the hospital. Prior to implementation of such a program, a number of issues need to be addressed, including state authorization, an expeditious method for donor organ retrieval, protocols for recipient selection and evaluation, and perioperative and follow-up care of the transplant recipient. Since July of 1983, 35 patients (27 men and eight women) have undergone orthotopic cardiac transplantation. Transplantation was undertaken for cardiomyopathy (30) or end-stage ischemic heart disease (5). The mean age was 38 years (range, 16 to 57 yrs). Distant organ procurement was used for 83 percent of patients; mean ischemic time was 164 min (range, 75 to 250 min). Current immunosuppressive regimen consists of oral cyclosporine (10 mg/kg) and prednisone. Mean follow-up was 10.3 months (range, two weeks to 27 months). Transient renal dysfunction appeared early in 15 patients. Six deaths have occurred: three from rejection, one from infection, one from metastatic prostate carcinoma, and one from pulmonary hemorrhage. All but three recent patients have been rehabilitated. These initial encouraging results are a result of careful planning, institutional commitment, adequate resources and, most importantly, a dedicated transplant team.

Surgical treatment of ischemic cardiomyopathy: Is it ever too late?

The question posed in the title of this report can be answered both “yes” and “no.” For most patients with severe congestive heart failure due to end-stage ischemic heart disease, however, conventional surgical treatment by myocardial revascularization or unconventional treatment by cardiac transplantation can offer genuine therapeutic benefit by ameliorating symptoms and extending survival. Although the results of standard coronary artery bypass operations in patients with ischemic cardiomyopathy are limited by the magnitude of preexistent left ventricular damage, retrospective analysis of medical and surgical treatment at our institution has shown that most patients with predominant angina pectoris preoperatively can be expected to be alive and free of limiting angina 5 years postoperatively. However, relief of symptoms in patients with predominant congestive heart failure preoperatively was considerably less impressive. Nevertheless, long-term survival rates for surgically treated patients were significantly superior to those for medically treated patients, due possibly to the prevention of fatal myocardial infarction. When the severity of left ventricular dysfunction and clinically evident congestive heart failure preclude a reasonable expectation of benefit from myocardial revascularization, carefully selected candidates with ischemic cardiomyopathy may undergo cardiac transplantation with expectation of survival rates of 59 ± 7 percent at 1 year and 49 ± 7 percent at 3 years, in conjunction with highly satisfactory symptomatic benefit and rehabilitation. Furthermore, the quality of results after cardiac transplantation is highly likely to improve in the near future because of more effective and less toxic immunosuppression. This development should expand the applicability of cardiac transplantation and render even more uncommon the designation of a patient with ischemic cardiomyopathy as inoperable because it is “too late.”