Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT.

Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio [HR] = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation.

Hematopoietic stem cell transplantation for primary immunodeficiency disease.

Hematopoietic stem cell transplantation is the definitive therapy for a variety of rare primary cellular immunodeficiency syndromes diagnosed in children. All primary immunodeficiencies benefit from early diagnosis and transplantation before the development of serious infections, which contribute to a significant increased risk of mortality following transplant. In the absence of a matched sibling, parental haplocompatible, matched unrelated donor and cord blood stem cells have all been utilized with varying degrees of success and immune reconstitution. The role of pretransplant conditioning in patients with SCID disease in terms of its effects upon T- and B-cell immune reconstitution and late effects is still under debate and will require further study.

Increasing mixed chimerism and the risk of graft loss in children undergoing allogeneic hematopoietic stem cell transplantation for non-malignant disorders.

We performed quantitative PCR-based serial chimerism testing of whole blood (WB) and CD3+ cells and retrospectively correlated the results of chimerism tests and the risk of graft loss in children undergoing transplant for non-malignant disorders. Twenty-four children were included in this study. All patients initially engrafted; subsequently, 12% lost the graft, 21% achieved complete donor chimerism and 67% had mixed chimerism (MC). Patients underwent delayed taper of cyclosporine (CsA) if they had MC. Overall survival was 87+/-7% (s.d.) at 5-years post transplant, and it was not affected by chimerism status. Both WB and CD3+ chimerism showed significant fluctuations with a peak in autologous cell signal occurring at a median of 7 months for WB and 2 months for CD3+ cells. Initial post transplant chimerism percentage in either WB or CD3+ lineage was not related to graft loss. Increasing MC to >30% host cells was seen in 33% of patients, and it was related to increased risk of graft loss, as previously published. However, 63% of children with increasing MC did not lose their graft. Additional studies of post transplant chimerism are required to improve our ability to accurately identify children at risk of graft loss following transplant for non-malignant disorders.

A defective Vkappa A2 allele in Navajos which may play a role in increased susceptibility to haemophilus influenzae type b disease.

The antibody response to H. influenzae type b (Hib) is pauciclonal, and is dominated by antibodies using the VkappaA2 gene. Navajos have a 5-10-fold increased incidence of Hib disease compared with control populations. We hypothesized that a polymorphism in one of the genes in this oligoclonal response may lead to increased disease susceptibility. Since the predominant A2+ anti-Hib antibodies have high avidity for Hib and can be unmutated, the A2 Vkappa gene was analyzed. Over half of the Navajos studied, but only one control individual, had a new allele of A2, termed A2b, with three changes from the published A2 germline sequence. One of the changes was in the recombination signal sequence, suggesting that the A2b allele might not undergo V-J rearrangement very frequently. This possibility was confirmed by analyzing the relative frequency of non-productive A2 rearrangements in A2a/b heterozygous Navajos. Many fewer A2b rearrangements were observed, showing that the A2b allele is defective in its ability to undergo rearrangement. The prevalence of this allele in Navajos may play a role in their increased susceptibility to invasive Hib disease. If so, it would underscore the importance of the germline Ig repertoire for protective antibody responses to pathogenic bacteria in unimmunized children.

Familial bone marrow monosomy 7. Evidence that the predisposing locus is not on the long arm of chromosome 7.

Loss of expression of a tumor-suppressing gene is an attractive model to explain the cytogenetic and epidemiologic features of cases of myelodysplasia and acute myelogenous leukemia (AML) associated with bone marrow monosomy 7 or partial deletion of the long arm (7q-). We used probes from within the breakpoint region on 7q-chromosomes (7q22-34) that detect restriction fragment length polymorphisms (RFLPs) to investigate three families in which two siblings developed myelodysplasia with monosomy 7. In the first family, probes from the proximal part of this region identified DNA derived from the same maternal chromosome in both leukemias. The RFLPs in these siblings diverged at the more distal J3.11 marker due to a mitotic recombination in one patient, a result that suggested a critical region on 7q proximal to probe J3.11. Detailed RFLP mapping of the implicated region was then performed in two additional unrelated pairs of affected siblings. In these families, DNA derived from different parental chromosome 7s was retained in the leukemic bone marrows of the siblings. We conclude that the familial predisposition to myelodysplasia is not located within a consistently deleted segment on the long arm of chromosome 7. These data provide evidence implicating multiple genetic events in the pathogenesis of myelodysplasia seen in association with bone marrow monosomy 7 or 7q-.

Hematopoietic cell transplantation for Chediak-Higashi syndrome.

We reviewed outcomes after allogeneic hematopoietic cell transplantation (HCT) in 35 children with Chediak-Higashi syndrome (CHS). Twenty-two patients had a history of the life-threatening accelerated phase of CHS before HCT and 11 were in accelerated phase at transplantation. Thirteen patients received their allograft from an human leukocyte antigen (HLA)-matched sibling, 10 from an alternative related donor and 12 from an unrelated donor. Eleven recipients of HLA-matched sibling donor, three recipients of alternative related donor and eight recipients of unrelated donor HCT are alive. With a median follow-up of 6.5 years, the 5-year probability of overall survival is 62%. Mortality was highest in those with accelerated phase disease at transplantation and after alternative related donor HCT. Only four of 11 patients with active disease at transplantation are alive. Seven recipients of alternative related donor HCT had active disease at transplantation and this may have influenced the poor outcome in this group. Although numbers are limited, HCT appears to be effective therapy for correcting and preventing hematologic and immunologic complications of CHS, and an unrelated donor may be a suitable alternative for patients without an HLA-matched sibling. Early referral and transplantation in remission after accelerated phase disease may improve disease-free survival.

Maternally transmitted HIV infection in children.

We evaluated 16 children at high risk for AIDS because of mothers infected with HIV. Two children were persistently seropositive and had laboratory and clinical evidence of HIV infection but had no detectable infectious HIV in their peripheral blood mononuclear cells (PBMC). Seven children, all of whom had clinical and laboratory evidence of HIV infection, were seropositive and virus culture-positive. One child who died at 10 months of age of candida septicemia was HIV antibody-negative but HIV was grown from cultures of his PBMC. Six children had no serologic or virologic evidence of HIV infection; of these, four who were asymptomatic with normal laboratory studies were HIV antibody-positive up to 12 months of age but became antibody-negative by 15 months of age. These observations indicate that: (1) as many as 60% of infants of infected mothers may be infected with HIV; (2) maternal antibody can result in a false-positive or false-negative diagnosis of HIV infection in infants exposed in utero or perinatally, and (3) the use of viral cultures for HIV is valuable for the early diagnosis of maternally transmitted HIV infection.

Use of polymerase chain reaction for the early detection of HIV infection in the infants of HIV-seropositive women.

Forty-two infants of HIV-seropositive women were evaluated to determine the value of polymerase chain reaction (PCR) in the early detection of HIV infection. All infants less than 6 months old had a simultaneous PCR and culture for HIV. There was an 88% concordance between the two techniques. PCR results showed an excellent correlation with clinical outcome; no PCR-negative patient has subsequently been found to be infected. Occasional false-positive or equivocal PCR results did occur. There was one false-negative culture. PCR is a rapid and sensitive diagnostic test for the early diagnosis of HIV infection in infants at risk, but at present it should be performed in conjunction with other diagnostic tests and good clinical follow-up.

Effect of thymosin on cellular immunity in old age.

Cell-mediated immunity (CMI) in a population of 28 well-nourished, disease-free old-age individuals (65--103 years) was compared to that of healthy young adult controls (22--41 years) and the effects in vitro of thymosin fraction 5 (TF5) evaluated. The number of T cells (T cell rosettes, TCR) in the peripheral blood was the same as controls. However, there was a significant depression in lymphocyte response to phytohemagglutinin (PHA) (p Less Than 0.005). Limiting dilution of the PHA response revealed an inherent defect in the function of those cells that are capable of responding to PHA. The formation of TCR from old-age subjects was similar to controls when incubated with TF5, i.e. there was no enhancement. When TF5 was incubated with old-age and normal control lymphocytes in the mixed lymphocyte reaction (MLR), there were significant increases in the responses in both (71 +/- 39% and 64 +/- 52%, respectively; p Greater Than 0.2). There was also a mitogenic effect of TF5 on resting lymphocytes which was significantly greater in the control than in the old-age population (p Less Than 0.002). Our results suggest that in old age: (1) there is no loss in absolute numbers of T lymphocytes; (2) there is a defect in the ability of individual lymphocytes to function; and (3) the response of lymphocytes in vitro to TF5 in forming TCR and in the MLR is statistically similar to young adult controls, and suggests that the decline in CMI with age is not due to a loss of thymosin-responsive cells.

Comparison of high-dose and low-dose intravenous immunoglobulin therapy in patients with primary immunodeficiency diseases.

To assess safety and efficacy of high-dose intravenous immunoglobulin therapy in patients with primary immunodeficiency syndromes we treated a group of 19 patients with a monthly dose of 400 mg/kg of reduced and alkylated, maltose-containing immunoglobulin (Gamimune, Cutter Biological, Berkeley, California) and compared their responses with a group of 16 patients receiving 100 mg/kg per month intravenously. Side effects observed were mild to moderately severe and similar in both groups. In one adult patient receiving the high dose a severe enough reaction developed during the first infusion to exclude her from the study. Serum IgG levels of patients receiving high-dose immunoglobulin showed a stepwise increase in both trough and peak values until a new plateau was reached after four to six infusions. None of the patients receiving the low dose showed such a stepwise increase. On average, serum IgG levels rose by approximately 250 mg/dl for each 100 mg/kg immunoglobulin infused. The mean catabolic rate of the infused IgG was estimated to be 26 days in patients receiving high-dose immunoglobulin infusions. We demonstrated that 400 mg/kg immunoglobulin given intravenously every four weeks to patients with immunodeficiency results in a substantial increase in serum IgG during the postinfusion period, suggesting persistence of specific antibody throughout the interval between infusions.

Toxicities of total-body irradiation for pediatric bone marrow transplantation.

PURPOSE: To determine the acute and late effects, including cognitive function, of total body irradiation (TBI) and chemotherapy for bone transplant (BMT) in children with immunodeficiency or hematologic disorders. METHODS AND MATERIALS: At UCSF, 15 children with immunodeficiency disorders and 58 children with leukemia received chemoradiotherapy between July 1982 and November 1993 and were evaluated for toxicity. Patients with severe combined immunodeficiency disorder (SCID) received 7 Gy TBI while leukemia patients received 12 Gy TBI. RESULTS: Eight immunodeficient patients (53%) are alive at 4 months to 11 years posttransplant. Acute toxicity was limited and treatment well tolerated. Most patients developed mild nausea and vomiting, skin rash, or erythema. Transient fever/chills, oral mucositis, and alopecia were noted in approximately 50% of patients. Seventy-three percent of all patients demonstrated acute liver dysfunction, but only four (27%) developed veno-occlusive disease. All children had decreased growth velocity but normal growth hormone levels. Other endocrinologic evaluations including adrenocorticotropic hormone (ACTH), cortisol, and thyroid hormones were normal. Only one evaluable girl had delayed puberty with late onset of secondary sexual characteristics. Neuropsychological testing demonstrated an intelligence quotient (IQ) reduction between the baseline and 1 year post-BMT, with some recovery at 3 years. Only one patient developed a clinically significant cataract. Thirteen percent of patients had chronic interstitial lung disease. Four children developed exostosis. Only 1 of the 15 children developed a second malignancy (acute myelogenous leukemia) at age 5, 51 months posttransplant for SCID. For patients with leukemia, similar toxicities were observed. Twenty-nine percent disease-free survival was noted with a mean follow-up of 4.7 years. Twenty-two percent had chronic interstitial lung disease and two patients were diagnosed with cataracts. Graft-vs.-host-disease (GVHD), pubertal development arrest, and delayed puberty were seen. One child developed papillary thyroid carcinoma, 49 months post-BMT. Similar neuropsychological testing decrements were also observed. CONCLUSION: Our experience suggests that intensive chemoradiotherapy, even at a young age, does not cause severe, acute, or late toxicities but does result in a small IQ decrement and the risk of secondary malignancy in children with long-term follow-up.

Transplantation of human peripheral blood stem cells into fetal rhesus monkeys (Macaca mulatta).

BACKGROUND: Methods for assessing engraftment efficiency have been explored in a primate xenogeneic model of in utero hematopoietic stem cell transplantation. METHODS: Human peripheral blood stem cells (PBSC) were obtained by leukapheresis from a human male donor after 4 days of administration of recombinant human granulocyte-colony stimulating factor (5 microg/kg/ day). PBSC were enriched for the CD34+ population with and without T-cell depletion. The resulting mononuclear cells consisted of two cell populations, one that was stem cell enriched (0.83% CD3+ cells, 95% CD34+; group 1) and one that was stem cell enriched and T-cell depleted (<0.03% CD3+ cells, 98% CD34+; group 2). Four fetal monkeys (two per group) received either two or four i.p. injections (approximately 5x10(6) cells/injection) via ultrasound guidance every other day over a 7-day period (gestational days 50, 52, 54, and 56). One fetus in each group also received i.p. recombinant human stem cell factor (25 microg/kg) and recombinant human granulocyte-colony stimulating factor (10 microg/kg) posttransplant every 10 days from gestational day 60-150. RESULTS: Four healthy newborns were delivered at term, and specimens were analyzed by polymerase chain reaction for the human Y chromosome (birth, monthly to 6 months; blood, marrow, progenitor assays). Polymerase chain reaction results were positive for all four newborns in all specimens assessed, and flow cytometric analysis for human CD45 in marrow showed engraftment ranging from 0.1-1.7%. There was no evidence of graft-versus-host disease in any of the animals. CONCLUSION: These studies show that (1) multilineage engraftment of human PBSC can be achieved in the fetal rhesus recipient, (2) the rhesus fetus appears to tolerate relatively high numbers of human CD3+ cells, and (3) healthy chimeric rhesus infants can be delivered at term after multiple in utero procedures.

Recruitment of engrafted donor cells postnatally into the blood with cytokines after in utero transplantation in mice.

BACKGROUND: We have previously shown that MHC-mismatched fetal liver cells can durably engraft in 45% of nondefective fetal mice, although male donor cells were found in the blood in only 8% of female recipients. We postulated that adult bone marrow stem cells would engraft similarly to fetal liver cells and that postnatal administration of cytokines would recruit donor cells into the peripheral circulation. METHODS: Bone marrow from C57BL/6 adult male mice was injected into allogeneic BALB/c or congenic C57BL/6 fetal recipients that were 11-13 days old. Engraftment was tested by quantitative polymerase chain reaction for the Y chromosome in female recipients (0.0001% sensitivity). Recipients were injected at 1-2 years of age with rat stem cell factor (SCF) and human granulocyte colony-stimulating factor (G-CSF) for 7 days and tested for donor cells in the blood. RESULTS: The overall engraftment rate (in the blood, spleen, or liver) was 44% in both female allogeneic and congenic bone marrow recipients. Of 49 recipients of bone marrow or fetal liver cells with no evidence of donor cells in the blood before injection, 29 (59%) developed circulating donor cells at some time after cytokine injection for up to 2 months. Twenty-seven of 49 animals were negative in the blood, liver, and spleen before cytokine therapy; 14 of 27 (52%) became positive in the blood after stem cell factor/granulocyte colony-stimulating factor injection. Tolerance to donor skin grafts was not altered by the mobilization of donor cells into the circulation. CONCLUSIONS: Adult bone marrow durably engrafts in nondefective mice at a rate similar to that previously obtained with fetal liver. Engrafted donor cells can be mobilized with cytokines into the circulation for up to 2 months even in animals with no evidence of donor cells in the blood, liver, or spleen. Based on these results we estimate that 70-75% of hematopoietically nondefective fetal mice engraft with MHC-mismatched fetal liver or adult bone marrow stem cells.

Increased engraftment and GVHD after in utero transplantation of MHC-mismatched bone marrow cells and CD80low, CD86(-) dendritic cells in a fetal mouse model.

BACKGROUND: Bone marrow transplantation (BMT) is the only known cure for a variety of inherited diseases and requires the administration of high doses of immunosuppressive and myeloablative therapy. Because the fetus is immunoincompetent early in gestation, in utero stem cell transplantation (IUT) could avoid the need for this toxic conditioning. A major limitation to date of IUT is the low level of engraftment and failure to induce tolerance. Dendritic cells (DC) are considered very potent antigen-presenting cells, but DC progenitors (pDC) are strongly tolerogenic. METHODS: We examined the effect of donor pDC on the degree of engraftment and tolerance induction after IUT. Bone marrow-derived pDC (CD80low, CD86-) from male C57BL/6 mice (H2b) were injected with and without donor bone marrow (BM) intraperitoneally into 13 to 15-day BALB/c (H2d) fetuses. Engraftment was determined by flow cytometry and quantitative polymerase chain reaction and tolerance by skin grafts and the mixed lymphocyte reaction. RESULTS: At 1-month posttransplant, mice that received BM+pDC showed a higher degree of engraftment (29+/-46%) than mice that received pDC-enriched cells or BM cells alone (0.11+/-0.70% and 1.71+/-1.66%, respectively, P<0.001). However, 5/19 recipients of BM+pDC died within 6 weeks; 4/5 had significant donor cell engraftment in blood and/or tissues. Also, these mice had evidence of graft-versus-host disease (GVHD). Two mice out of 15 long-term survivors in the BM+pDC group had virtually complete replacement of host with donor hematopoietic cells. Skin grafts and mixed lymphocyte reaction studies showed no durable tolerance induction other than in the two fully engrafted recipients of BM+pDC. CONCLUSIONS: These results suggest that donor pDC, along with donor BM, can have a significant impact on engraftment of MHC-mismatched donor cells associated with an increased incidence of GVHD. However, marrow-derived pDC do not result in an increase in tolerance induction in utero even when microchimerism is present.

Maternal transmission of acquired immune deficiency syndrome.

Acquired immune deficiency syndrome (AIDS) has been reported in previously healthy homosexual or bisexual males, intravenous drug users, heterosexual men with hemophilia, and Haitians. The finding of heterosexual hemophiliacs with AIDS has raised the possibility of a transmittable blood-borne agent as a cause of this disease. We have found three female half-siblings who had clinical and laboratory evidence for AIDS. All three had evidence of abnormal in vitro cellular immunity; two had chronic active Epstein-Barr virus infection and lymphadenopathy; all three had chronic cutaneous Candida sp infection; and two had Pneumocystis carinii pneumonia. Their mother is a prostitute/drug addict with abnormal T-cell immunity including clinical and laboratory findings of mucocutaneous candidiasis. Histocompatibility typing is consistent with the history of different fathers for each child. Immunologic studies in one child evaluated prospectively from birth were abnormal by 2 months of age. These findings and the clinical histories indicate AIDS and strongly suggest vertical transmission of an agent(s) during the perinatal period.

A prospective study of cognitive functioning following low-dose cranial radiation for bone marrow transplantation.

This study prospectively examined the effects of low doses of cranial irradiation on psychological development in children. The subjects were 22 children receiving bone marrow transplantation. Fifteen children receiving cranial doses ranging from 350 to 1200 cGy as part of their conditioning regimen were contrasted to seven children who were not irradiated. Measures of intellectual and psychosocial development were administered to all subjects prior to transplant and again at one-year posttransplant. There were no decrements in psychological functioning at the one-year follow-up, regardless of the dose of cranial radiation received or the age at which radiation was administered. In addition, there were no significant differences in test scores relative to baseline in a smaller cohort of children followed up for 3 years. Although no significant between-group findings were found, examination of individual cases revealed a high degree of variability, with decrements in IQ of 10 points or more found in 7 children at the one-year follow-up. Findings suggest that doses less than 1500 cGy may prove to be relatively well tolerated with respect to long-term cognitive and psychosocial development, even in young children, although caution is urged in light of the limited length of follow-up.

Pneumococcal polysaccharide immunization in infants and children.

By using indirect hemagglutination, the antibody responses of normal infants and children to an octavalent pneumococcal vaccine that contained pneumococcal polysaccharide types 1, 3, 6, 7, 14, 18, 19, and 23 were evaluated. By 2 years of age, there was a significant rise in hemagglutination titers to all the polysaccharide types, except type 19. By 6 to 8 months of age, five of the eight types of pneumococcal polysaccharides tested resulted in up to 60% responders and, by 2 years, a significant number responded to all pneumococcal polysaccharide types in the vaccine. Pneumococcal polysaccharide type 3 resulted in a significant antibody response as early as 3 months of age, whereas type 19 never resulted in a significant antibody response. Except for type 3, it seemed that when the other pneumococcal polysaccharides tested produced an antibody response, the degree of resonse did not subsequently change significantly with increasing age. The relationship of antibody response to age for pneumococcal polysaccharides is similar to that found for other polysaccharide vaccines. Based on the results of our study, we would recommend immunization with pneumococcal vaccine at 6 months of age with repeat immunization at 2 years of age, especially in high-risk children.

Noninvasive detection of hypoxic myocardium using fluorine-18-fluoromisonidazole and positron emission tomography.

Fluoromisonidazole (FMISO) is metabolically trapped in viable cells as a function of reduced cellular pO2. Therefore [18F]-FMISO is potentially useful for evaluating patients with hypoxic but viable myocardium. The goal of this study was to investigate [18F]FMISO uptake in ischemic myocardium non-invasively using positron emission tomography (PET). Studies were performed in 10 open-chest dogs subjected to either complete (Group 1, n = 5) or partial (Group 2, n = 5) occlusion of the left anterior descending coronary artery. The tracer was administered by intravenous bolus following the onset of ischemia and serial PET images were acquired for the next 4 hr. In Group 1, viability was assessed using histochemical staining (nitroblue tetrazolium, NBT) and 99mTc-pyrophosphate (Tc-PYP). In Group 2, viability was assessed using measurements of regional wall motion, histochemical staining and histology (two animals). In each study, PET images obtained at times between 2 and 4 hr postinjection showed specific enhancement of tracer activity in the distal anterior wall and apex of the left ventricle. At 4 hr, the tissue-to-blood pool count ratio was significantly higher in ischemic regions; 1.8 +/- 0.4 for Group 1 and 1.6 +/- 0.2 for Group 2 versus 1.0 +/- 0.1 in nonischemic regions. Postmortem tissue sampling of Group 1 hearts showed significant FMISO retention in samples without evidence for infarction, either by NBT or Tc-PYP deposition, as well as in more severely ischemic regions. In Group 2 animals, FMISO was retained in myocardial regions with reduced blood flow (microspheres), which exhibited improved contraction following reperfusion. We conclude that PET imaging of [18F]FMISO is a promising technique for the noninvasive identification of viable hypoxic myocardium.

Estimation of inferobasal myocardial infarct size by late activation abnormalities of the QRS complex.

This report describes the relation of myocardial infarct (MI) size in the left ventricular inferobasal wall, measured at necropsy, to late activation abnormalities of the QRS complex, measured by computerized spatial vectorcardiography. Fifteen patients with single inferobasal MIs and 10 patients with no evidence of heart disease were studied. The percentage of MI in the inferobasal wall was significantly related to the vectorcardiographic abnormalities noted late (i.e., 31 +/- 13 ms before the end of the QRS waveform) (r = 0.96, p less than 0.00001). The integral of the vector magnitudes during late abnormal activation significantly predicted the amount of MI in the basal inferior wall (r = 0.88) and in the basal inferior wall plus the outer, subepicardial half of the transmural middle inferior, lateral and inferoseptal walls (r = 0.91). The additional information obtained from late activation of the QRS complex contributed more significance to the estimation of the left ventricular inferobasal MI size than the abnormalities commonly noted during early activation (i.e., during the Q wave).

Validation of a computerized QRS criterion for estimating myocardial infarction size and correlation with quantitative morphologic measurements.

This replication study describes the relation of myocardial infarction (MI) size, measured at autopsy, to initial and late QRS abnormalities, measured by computerized spatial vectorcardiography. Thirty-one patients with MIs of differing ages and left ventricular locations and 24 patients with no evidence of heart disease were studied. The percent volume of MI was significantly estimated by the initial QRS abnormalities (r = 0.94, p less than 0.00001). The 2 regression equations from the previous training set and from this present test set were compared to verify validity of the criterion, the integral of magnitudes of spatial vectors during initial abnormal depolarization to estimate MI size. There was not a significant difference between the 2 intercepts, the 2 slopes, the 2 straight-line regressions or the 2 correlation coefficients. The additional information obtained from late QRS abnormalities contributed little to improve estimation of size of multiple MIs of differing ages and left ventricular locations, but accurately predicted (r = 0.87) the size in single inferobasal MI. The results indicate that vectorcardiographic measurements of early activation abnormalities is a valid criterion to estimate MI size.