Physical examination for exclusion of hemodynamically important right ventricular infarction

Fifty-three consecutive patients with inferior myocardial infarction were evaluated prospectively, by physical examination and right heart catheterization within 36 hours of the onset of symptoms, to determine whether physical findings can separate such patients into those with and without associated right ventricular infarction. Hemodynamic findings consistent with right ventricular infarction were defined as right atrial pressure of 10 mm Hg or greater and a right atrial: pulmonary artery wedge pressure ratio of 0.80 or greater. Eight patients (Group 1) had hemodynamic evidence of right ventricular infarction, whereas 45 patients (Group 2) did not meet these criteria. Group 1, compared with Group 2, had a lower cardiac index (1.8 +/- 0.3 versus 2.6 +/- 0.6 L/min X m2, p less than 0.001), and a lower right ventricular stroke work index (4.1 +/- 3.6 versus 7.3 +/- 3.2 g X m/m2, p less than 0.05). An elevated jugular venous pressure of 8 cm H2O or more was seen in 7 of 8 Group 1 and 14 of 45 Group 2 patients (p less than 0.01). In addition, a Kussmaul's sign, substantiated by hemodynamic findings, was seen in all 8 Group 1 and in no Group 2 patients (p less than 0.001). The absence of both an elevated jugular venous pressure and a Kussmaul's sign in patients with inferior myocardial infarction makes the presence of a hemodynamically significant right ventricular infarction highly unlikely.     

Suppression of apoptosis in hematopoietic factor-dependent progenitor cell lines by expression of the FAC gene

Fanconi anemia (FA) is a genetically heterogeneous, inherited blood disorder characterized by bone marrow failure, congenital malformations, and a predisposition to leukemias. Because FA cells are hypersensitive to DNA cross-linking agents and have chromosomal instability, FA has been viewed as a disorder of DNA repair. However, the exact cellular defect in FA cells has not been identified. Sequence analysis of the gene defective in group C patients (FAC) has shown no significant homologies to other known genes. The FAC protein has been localized to the cytoplasm, indicating that FAC may either play an indirect role in DNA repair or is involved in a different cellular pathway. Recent evidence has indicated that FA cells may be predisposed to apoptosis, especially after treatment with DNA cross-linking agents. The demonstration that genes can suppress apoptosis has been accomplished by overexpression of such genes in growth factor-dependent cell lines that die by apoptosis after factor withdrawal. Using retroviral-mediated gene transfer, we present evidence that expression of FAC in the hematopoietic factor-dependent progenitor cell lines 32D and MO7e can suppress apoptosis induced by growth factor withdrawal. Flow cytometry and morphologic analysis of propidium iodide stained cells showed significantly lower levels of apoptosis in FAC-retroviral transduced cells after growth factor deprivation. Expression of FAC in both cell lines promoted increased viability rather than proliferation, which is consistent with other apoptosis-inhibiting genes such as Bcl- 2. These findings imply that FAC may act as a mediator of an apoptotic pathway initiated by growth factor withdrawal. Furthermore, the congenital malformations and hematologic abnormalities characterizing FA may be related to an increased predisposition of FA progenitor cells to undergo apoptosis, particularly in the absence of extracellular signals.     

Factors that affect human hemopoiesis are produced by T-cell growth factor dependent and independent cultured T-cell leukemia-lymphoma cells

Some laboratory results and clinical situations suggest that human T cells may be important in the regulation of growth of hematopoietic cells. Since the discovery of T-cell growth factor (TCGF), systems are now available for the long-term specific in vitro propagation of mature normal or neoplastic human T cells, providing an opportunity to study the influence of T cells on hematopoiesis. Recently, 24 cell lines from patients with cutaneous T-cell lymphoma (CTCL) and T-cell acute lymphoblastic leukemia (T-ALL) were grown with TCGF and then assessed for release of humoral factors that affect hematopoiesis. Conditioned media (CM) from these cell lines were tested for erythroid burst- promoting activity (BPA) and granulocyte colony-stimulating activity (CSA). BPA was detected in CM from 3/6 cultures of T-ALL patients and 4/6 CTCL cultures. CSA was found in the CM from 6/8 cultures of T-ALL patients, 7/12 CTCL cultures, and 3/4 CTCL cell lines that become independent of exogenous TCGF for growth. The CSA from several of the neoplastic T-cell cultures stimulated high levels of eosinophil colonies, a possible source of the eosinophilia seen in these patients. The ability of continuously proliferating human T lymphocytes, which retain functional specificity and responsiveness to normal humoral regulation, to produce factors that directly or indirectly stimulate myeloid and erythroid colony formation lends further credence to the role of T lymphocytes in regulating hematopoiesis.     

Relation between maximum time-varying elastance pressure-volume areas and myocardial oxygen consumption in dogs

To establish whether pressure-volume areas (PVAs) calculated using the maximum time-varying elastance (Emax) have a relation with myocardial oxygen consumption (MVO2) that improves on other indexes of myocardial oxygen demand, we studied nine dogs of either sex weighing 19-39 kg, which were instrumented with a micromanometer left ventricular (LV) catheter and a Wilton-Webster coronary sinus flow catheter and had red blood cells tagged with technetium-99m for radionuclide angiography. Hemodynamics, coronary sinus flow determinations, and radionuclide angiograms were obtained under control conditions and during three to five steady-state loading conditions (mean +/- SD, 5.6 +/- 0.7). Isochronal pressure-volume data points from each pressure-volume loop were subjected to linear regression analysis to calculate Emax. The Emax relations, diastolic curves, and systolic portions of each pressure-volume loop were used to obtain calibrated PVAs. The Emax PVA (mm Hg.ml.beat-1.100 g-1) and MVO2 (ml O2.beat-1.100 g-1) values correlated in each animal (r = 0.77 to 0.99). Their slopes averaged (3.48 +/- 1.68) x 10(-5) ml O2.mm Hg-1.ml-1, and their y-axis intercepts averaged 0.07 +/- 0.04 ml O2.beat-1.100 g-1. When the MVO2 relations were compared with Emax PVA, LV systolic pressure-rate product, LV stroke work, and a modification of the LV pressure-work index, the Emax PVA, LV systolic pressure-rate product, and LV pressure-work index had similar relations with MVO2, whereas LV stroke work was a weaker index of MVO2 (p less than 0.05 versus Emax PVA). This occurred because the Emax PVA:MVO2 slopes and y-axis intercepts differed in each dog, which was due to differences in basal LV contractility. The Emax PVA:MVO2 slopes correlated with Emax (r = 0.73, p less than 0.05), and the y-axis intercepts were also weakly related to Emax (r = 0.48, p = 0.19). We conclude that the Emax PVAs calculated using data acquisition techniques that are clinically applicable have relations with MVO2 that in general do not improve on other indexes of myocardial oxygen demand in this animal preparation.     

Rationale, design, and methods for a pivotal randomized clinical trial for the assessment of a cardiac support device in patients with New York health association class III-IV heart failure

BACKGROUND: Heart failure remains a progressive disease with incremental morbidity and mortality despite optimal medical therapy. A growing body of evidence suggests that progressive left ventricular (LV) remodeling is directly related to a deterioration in LV performance and untoward clinical outcomes for heart failure patients. Preclinical and early phase I clinical studies with the CorCap Cardiac Support Device (CSD), a passive cardiac support device that prevents cardiac remodeling, have shown that it is safe and is associated with improvements in LV structure and function, as well as patient symptomatology. METHODS AND RESULTS: The Acorn Pivotal Trial is a pivotal prospective, randomized, evaluation of the CorCap CSD in patients with New York Heart Association class III-IV heart failure. Patients will be enrolled into one of two different strata. Patients who require a mitral valve repair/replacement (MVR) will fall into the "MVR stratum" and will be randomized to either treatment (MVR surgery plus the CSD) or control (MVR surgery alone). Patients who do not have a clinical indication for MVR surgery will fall into the "no-MVR stratum" and will also be randomized to either treatment (CSD implant plus optimal medical therapy) or control (optimal medical therapy alone). A total of 300 patients (150 treatment and 150 control) will be enrolled. The primary endpoint of the trial is the change in clinical status from baseline to the end of the efficacy phase (1 year), as determined by a clinical composite score. Patients will be classified as improved, worsened, or unchanged based upon patient vital status, the occurrence of a major cardiac procedure indicative of heart failure progression, and a change in the assessment of New York Heart Association functional class. CONCLUSIONS: The Acorn Pivotal Trial will formally test the hypothesis that preventing LV remodeling using a passive cardiac support device will favorably impact the untoward natural history of heart failure and thus represents an important departure from all previous medical and device studies that have been reported to date.