Citations

Although resistant hypertension affects a minority of all hypertensives, this group continues to experience disproportionately high cardiovascular event rates despite newer antihypertensive agents. Hypertension represents an imbalance of hemodynamic forces within the circulation, usually characterized by elevated systemic vascular resistance. We studied the utility of serial hemodynamic parameters in the selection and titration of antihypertensive medication in resistant hypertensive patients using highly reproducible noninvasive measurements by thoracic bioimpedance. Resistant hypertension patients (n=104) were randomized to drug selection based either on serial hemodynamic (HD) measurements and a predefined algorithm or on drug selection directed by a hypertension specialist (SC) in a 3-month intensive treatment program. Blood pressure was lowered by intensified drug therapy in both treatment groups (169±3/87±2 to 139±2/72±1 mm Hg HD versus 173±3/91±2 to 147±2/79±1 mm Hg SC, P <0.01 for systolic and diastolic BP), using similar numbers and intensity of antihypertensive medications. Blood pressures were reduced further for those treated according to hemodynamic measurements, resulting in improved control rates (56% HD versus 33% SC controlled to ≤140/90 mm Hg, P <0.05) and incremental reduction in systemic vascular resistance measurements. Although the number of patients taking diuretics did not differ between groups, final diuretic dosage was higher in the hemodynamic cohort. Our results demonstrate superior blood pressure control using a treatment algorithm and serial hemodynamic measurements compared with clinical judgment alone in a randomized prospective study. Our measurements of thoracic fluid volume support occult volume expansion as a mediator of antihypertensive drug resistance and use of impedance measurements to guide advancing diuretic dose and adjustment of multidrug antihypertensive treatment.

Background — CD4 T lymphocytes accumulate in unstable plaque. The direct and indirect involvement of these T cells in tissue injury and plaque instability is not understood. Methods and Results — Gene profiling identified perforin, CD161, and members of the killer-cell immunoglobulin-like receptors as being differentially expressed in CD4 + CD28 null T cells, a T-cell subset that preferentially infiltrates unstable plaque. Frequencies of CD161 + and perforin-expressing CD4 T cells in peripheral blood were significantly increased in patients with unstable angina (UA). CD161 appeared on CD4 + CD28 null T cells after stimulation, suggesting spontaneous activation of circulating CD4 T cells in UA. Perforin-expressing CD4 + T-cell clones from patients with UA exhibited cytotoxic activity against human umbilical vein endothelial cells (HUVECs) in redirected cytotoxicity assays after T-cell receptor triggering and also after stimulation of major histocompatibility complex class I–recognizing killer-cell immunoglobulin-like receptors. HUVEC cytolysis was dependent on granule exocytosis, as demonstrated by the paralyzing effect of pretreating CD4 + CD28 null T cells with strontium. Incubation of HUVECs with C-reactive protein (CRP) increased HUVEC lysis in a dose-dependent fashion. Conclusions — In patients with UA, CD4 T cells undergo a change in functional profile and acquire cytotoxic capability. Cytotoxic CD4 T cells effectively kill endothelial cells; CRP sensitizes endothelial cells to the cytotoxic process. We propose that T-cell–mediated endothelial cell injury is a novel pathway of tissue damage that contributes to plaque destabilization. The sensitizing effect of CRP suggests synergy between dysregulated T-cell function and acute phase proteins in acute coronary syndromes.

Background — Electron beam computed tomography is an accurate, noninvasive method to detect and quantify coronary artery calcification (CAC), a marker of subclinical and clinical coronary artery atherosclerosis. CAC quantity predicts future coronary artery disease end points in asymptomatic adults, but measured risk factors explain less than half the variability in CAC quantity. Although several candidate genes for CAC have been identified, the relative importance of genetic influences on CAC quantity has not been assessed in asymptomatic adults in a community. Methods and Results — We quantified the relative contributions of measured risk factors and genetic influences on CAC quantity measured by electron beam computed tomography in 698 asymptomatic white adults from 302 families. Before adjusting for any risk factors, 43.5% of the variation in CAC quantity was attributable to genetic factors ( P =0.0007). Independent predictors of CAC quantity were identified with stepwise linear regression. After adjusting for these risk factors, including age, sex, fasting glucose level, systolic blood pressure, pack-years of smoking, and LDL cholesterol, 41.8% of the residual variation in CAC quantity was attributable to genetic factors ( P =0.0003). Conclusions — These results demonstrate the importance of genetic factors in subclinical coronary atherosclerosis variation as measured by CAC quantity. The presence of genetic effects suggests that unknown genes that influence CAC quantity are yet to be identified.

Background — In patients undergoing percutaneous coronary intervention (PCI) in the modern era, the incidence and prognostic implications of acute renal failure (ARF) are unknown. Methods and Results — With a retrospective analysis of the Mayo Clinic PCI registry, we determined the incidence of, risk factors for, and prognostic implications of ARF (defined as an increase in serum creatinine [Cr] >0.5 mg/dL from baseline) after PCI. Of 7586 patients, 254 (3.3%) experienced ARF. Among patients with baseline Cr <2.0, the risk of ARF was higher among diabetic than nondiabetic patients, whereas among those with a baseline Cr >2.0, all had a significant risk of ARF. In multivariate analysis, ARF was associated with baseline serum Cr, acute myocardial infarction, shock, and volume of contrast medium administered. Twenty-two percent of patients with ARF died during the index hospitalization compared with only 1.4% of patients without ARF ( P <0.0001). After adjustment, ARF remained strongly associated with death. Among hospital survivors with ARF, 1- and 5-year estimated mortality rates were 12.1% and 44.6%, respectively, much greater than the 3.7% and 14.5% mortality rates in patients without ARF ( P <0.0001). Conclusions — The overall incidence of ARF after PCI is low. Diabetic patients with baseline Cr values <2.0 mg/dL are at higher risk than nondiabetic patients, whereas all patients with a serum Cr >2.0 are at high risk for ARF. ARF was highly correlated with death during the index hospitalization and after dismissal.

Rituximab is a chimeric murine/human monoclonal antibody that binds to CD20 on B lymphocytes. Although binding of the Fab domain may induce apoptosis, the Fc domain recruits immune effector functions to mediate cell lysis. Interleukin-12 (IL-12) facilitates cytolytic T-cell responses, enhances the lytic activity of natural killer (NK) cells, and induces the secretion of interferon γ (IFN-γ) by both T and NK cells. Therefore, the hypothesis was considered that combining IL-12 with rituximab would augment the immune-mediated cell lysis induced by rituximab. A phase 1 study of IL-12 in combination with rituximab was conducted in 43 adults with B-cell lymphoma to determine the optimal immunologic dose of this combination. Rituximab was administered at a dose of 375 mg/m2 by intravenous infusion weekly for 4 weeks, and IL-12 was given subcutaneously twice weekly. The starting dose of IL-12 was 30 ng/kg and this was escalated to 500 ng/kg. Constitutional symptoms and liver enzyme elevations at 500 ng/kg of IL-12 were dose limiting. A greater than 20-fold increase in the serum levels of IFN-γ and a 2.5- to 5-fold increase in inducible protein 10 (IP-10) levels was seen at IL-12 doses of 100 ng/kg or greater. Objective responses occurred in 29 of the 43 patients (69%), with 8 of 11 complete responses seen at IL-12 doses of 300 ng/kg or greater. The optimal immunologic dose of IL-12 in combination with rituximab was determined to be 300 ng/kg subcutaneously twice weekly starting on day 2. These data suggest that IL-12 and rituximab is an active combination and further studies of this combination in B-cell non-Hodgkin lymphoma are warranted.

AbstractAutologous stem cell transplantation (ASCT) improves survival in patients with previously untreated multiple myeloma (MM) and relapsed, chemotherapy-sensitive, aggressive non-Hodgkin lymphoma (NHL). Lower relapse rates seen in allogeneic stem cell transplantation have been related to early absolute lymphocyte count (ALC) recovery as a manifestation of early graft-verus-tumor effect. In ASCT, the relation between ALC recovery and clinical outcomes in MM and NHL was not previously described. This is a retrospective study of patients with MM and NHL who underwent ASCT at the Mayo Clinic between 1987 and 1999. The ALC threshold was determined at 500 cells/μL on day 15 after ASCT. The study identified 126 patients with MM and 104 patients with NHL. The median overall survival (OS) and progression-free survival (PFS) times for patients with MM were significantly longer in patients with an ALC of 500 cells/μL or more than patients with an ALC of fewer than 500 cells/μL (33 vs 12 months,P &lt; .0001; 16 vs 8 months, P &lt; .0003, respectively). For patients with NHL, the median OS and PFS times were significantly longer in patients with an ALC of 500 cells/μL or more versus those with fewer than 500 cells/μL (not reached vs 6 months, P &lt; .0001; not reached vs 4 months,P &lt; .0001, respectively). Multivariate analysis demonstrated day 15 ALC to be an independent prognostic indicator for OS and PFS rates for both groups of patients. In conclusion, ALC is correlated with clinical outcome and requires further study.

Derivatives of the Edmonston-B strain of measles virus (MV-Ed) are safe, live attenuated measles virus (MV) vaccines that have been used worldwide for more than 30 years. The cytoreductive potential of MV-Ed has been investigated in murine models of both aggressive and indolent B-cell lymphoma in severe combined immunodeficient (SCID) mice. The rationale for these studies was generated by experience with viral fusogenic membrane glycoproteins as cytotoxic genes and the recognition of the potential of replicating viruses in the treatment of human malignancy. Intratumoral injection of both unmodified MV-Ed and a strain of MV-Ed genetically modified by the addition of a β-galactosidase reporter gene (MVlacZ) induced regression of large established human lymphoma xenografts, in contrast to control therapy with UV-inactivated virus, in which all tumors progressed. The antitumor effect still occurred in the presence of passively transferred anti-MV antibody. Intravenous administration of MV also resulted in considerable slowing of tumor progression. Analysis of sections of residual tumor confirmed replication of MV within the tumors. Thus, the vaccine strain of MV mediates regression of large, established human B-cell lymphoma xenografts in SCID mice, and proof of principle is established that MV is oncolytic for lymphomas in vivo. Attenuated MVs may have value as a novel replicating-virus therapy for this group of disorders.

▪ Abstract Chronic azotemic renovascular disease is common in patients with atherosclerosis. Its prevalence appears to be increasing in the aging population. How often it is the primary cause of end-stage renal disease (ESRD) is not yet certain. Some studies suggest that 10%–40% of elderly hypertensive patients with newly documented ESRD and no demonstrable primary renal disease have significant renal artery stenosis (RAS). Atherosclerotic vascular occlusive disease of the renal arteries does progress, but current rates of progression and occlusion are lower than those reported a decade ago. Methods of identifying patients whose renal function is at true risk from vascular occlusive disease and determining who will benefit from intervention remain elusive. The presence of RAS in an azotemic patient can be assessed with noninvasive and risk-free radiologic techniques, including Duplex doppler velicometry and magnetic resonance angiography. Functional tests that predict the change in renal function after revascularization are not yet available. However, a renal length of greater than 7.5 cm in the absence of renal cysts and a short history of renal functional deterioration indicate a good prognosis. Patients with recent deterioration in renal function, those with bilateral renal artery stenosis or stenosis to a single functioning kidney, those with flash pulmonary edema, advanced chronic renal failure, or ESRD (who have much to gain), those with reversible azotemia during angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor antagonist (ARB) therapy, and those whose conditions cannot be managed medically should be considered for revascularization. Results from recent controlled clinical trials of the response to percutaneous transluminal renal artery angioplasty (PTRA) and stenting indicate that improvement in blood pressure control or renal function is not a predictable outcome of renal revascularization. In azotemic groups, 25%–30% of patients achieve important recovery of renal function. Thus, significant progress has been made recently in determining whether RAS is a frequent, treatable cause of renal failure. The decision to recommend revascularization remains a difficult balance between the risks and expense of the procedure and the undoubted benefits that accrue if renal function is successfully stabilized.

ABSTRACT In vitro surveys of antimicrobial resistance among clinically important anaerobes are an important source of information that can be used for clinical decisions in the choice of empiric antimicrobial therapy. This study surveyed the susceptibilities of 556 clinical anaerobic isolates from four large medical centers using a broth microdilution method. Piperacillin-tazobactam was the only antimicrobial agent to which all the isolates were susceptible. Similarly, imipenem, meropenem, and metronidazole were highly active (resistance, <0.5%), whereas the lowest susceptibility rates were noted for penicillin G, ciprofloxacin, and clindamycin. For most antibiotics, blood isolates were less susceptible than isolates from intra-abdominal, obstetric-gynecologic, and other sources. All isolates of the Bacteroides fragilis group were susceptible to piperacillin-tazobactam and metronidazole, while resistance to imipenem and meropenem was low (<2%). For these same isolates, resistance rates (intermediate and resistant MICs) to ampicillin-sulbactam, cefoxitin, trovafloxacin, and clindamycin were 11, 8, 7, and 29%, respectively. Among the individual species of the B. fragilis group, the highest resistance rates were noted among the following organism-drug combinations: for clindamycin, Bacteroides distasonis and Bacteroides ovatus ; for cefoxitin, Bacteroides thetaiotaomicron, B. distasonis , and Bacteroides uniformis; for ampicillin-sulbactam, B. distasonis, B. ovatus , and B. uniformis ; and for trovafloxacin, Bacteroides vulgatus . For the carbapenens, imipenem resistance was noted among B. fragilis and meropenem resistance was seen among B. fragilis, B. vulgatus , and B. uniformis . With few exceptions all antimicrobial agents were highly active against isolates of Prevotella, Fusobacterium, Porphyromonas , and Peptostreptococcus . These data further establish and confirm that clinically important anaerobes can vary widely in their antimicrobial susceptibilities. Fortunately most antimicrobial agents were active against the test isolates. However, concern is warranted for what appears to be a significant increases in resistance to ampicillin-sulbactam and clindamycin.