Long-term prognostic value of coronary calcification detected by electron-beam computed tomography in patients undergoing coronary angiography.

BACKGROUND: Electron-beam CT (EBCT) quantification of coronary artery calcification (CAC) allows noninvasive assessment of coronary atherosclerosis. We undertook a follow-up study to determine whether CAC extent, measured at the time of angiography by EBCT, predicted future hard cardiac events, comprising cardiac death and nonfatal myocardial infarction (MI). We also assessed the potential of selected coronary artery disease (CAD) risk factors, prior CAD event history (MI or revascularization), and angiographic findings (number of diseased vessels and overall disease burden) to predict subsequent hard events. METHODS AND RESULTS: Two hundred eighty-eight patients who underwent contemporaneous coronary angiography and EBCT scanning were contacted after a mean of 6.9 years. Vital status and history of MI during follow-up were determined. Cox proportional hazards models were used to compare the predictive ability of CAC extent with selected CAD risk factors, CAD event history, and angiographic findings. Median CAC score was 160 (range 0 to 7633). The 22 patients who experienced hard events during follow-up were older and had more extensive CAC and angiographic disease (P<0.05). Only 1 of 87 patients with CAC score <20 experienced a subsequent hard event during follow-up. Event-free survival was significantly higher for patients with CAC scores <100 than for those with scores >/=100 (relative risk 3.20; 95% CI 1.17 to 8.71). When a stepwise multivariable model was used, only age and CAC extent predicted hard events (risk ratios 1.72 and 1.88, respectively; P<0.05). CONCLUSIONS: In patients undergoing angiography, CAC extent on EBCT is highly predictive of future hard cardiac events and adds valuable prognostic information.

Gene therapy for myocardial angiogenesis: has it come of age?

Vasculogenesis and angiogenesis are the processes responsible for the development of the circulatory system during embryonic and adult life. Vasculogenesis occurs during embryogenesis while angiogenesis refers to blood vessel formation from any preexisting vasculature. Postnatal angiogenesis resumes during reproduction, wound healing, and ischemia. Excess blood vessel formation may contribute to initiating and maintaining many diseases such as chronic inflammatory disorders, tumor growth, restenosis, and atherosclerosis. In contrast. insufficient blood vessel formation is responsible for tissue ischemia, as in coronary artery disease. An increasing number of patients with advanced coronary artery disease remain symptomatic despite maximal interventional, surgical or medical treatment. Ideally, they would benefit most from additional arterial blood supply to ischemic areas of myocardium. Therapeutic angiogenesis, the ability to induce the growth of new blood vessels, is one of the most intriguing new frontiers in interventional cardiology for this growing patient group. Several approaches are currently undergoing intensive experimental investigations or have already entered early clinical trials involving either local angiogenic peptide administration or the transfection of angiogenic genes. Gene therapy for therapeutic myocardial angiogenesis is the most promising synthesis of two emerging technologies. In the following article, we will review the fundamental pathophysiological concepts of gene-based angiogenic therapy, the technical approaches and delivery systems, and the results of the first clinical trials. We will also discuss the controversies and unresolved issues of this new revascularization therapy.

Decreased alpha-adrenergic response in the intestinal microcirculation after "two-hit" hemorrhage/resuscitation and bacteremia.

BACKGROUND: The two-hit theory of multiple organ dysfunction syndrome proposes that an initial insult primes the host for an altered response to subsequent stimuli. We have previously documented enhanced dilator tone in the small intestine after a two-hit insult; however, the effects on vasoconstrictor function are unknown. We postulated that prior hemorrhage and resuscitation followed by bacteremia would alter microvascular responsiveness to alpha-adrenergic stimulation. METHODS: Male Sprague-Dawley rats underwent fixed-volume hemorrhage with resuscitation (H/R) or sham procedure (Sham). At 24 or 72 h, in vivo videomicroscopy of the small intestine was performed (inflow A1 and premucosal A3 arterioles). Constrictor function was assessed by topical application of norepinephrine (NE; 10(-8)-10(-6) M) before and 1 h after intravenous Escherichia coli or saline. RESULTS: Sham, 24 or 72 h H/R, and E. coli alone produced no significant changes in A1 or A3 response to NE. Sequential H/R + E. coli resulted in decreased constrictor response in both A1 (72 h H/R + E. coli-38% from baseline vs Sham - 54%, P < 0.05) and A3 arterioles (-8% vs -51%, P < 0.05) at high doses of NE (10(-6) M). CONCLUSIONS: Prior H/R primes the intestinal microvasculature for an altered response during a subsequent stress and these effects persist for up to 72 h following H/R. Sequential insults in this two-hit model caused marked hyporesponsiveness to NE. These alterations in control of microvascular tone might contribute to the hemodynamic compromise of sepsis, impair mucosal blood flow, and contribute to the development of MODS.

Modification of molecular events in coronary restenosis using coated stents: The Mayo Clinic Approach.

Restenosis remains the major problem in interventional cardiology today. The intracoronary stent is an indispensable part of the interventional coronary practice. Restenosis rates, using current third generation devices in straightforward lesions are now less than 10%. Advances in stenting have had a remarkable effect on the safety and efficacy of clinical practice. Now that stents are easily deployed, and have shown substantive clinical impact, questions arise about the future of stenting. Answers to this question centre on several remaining problems with current stent technology and interaction with the biology of coronary arteries. One method to accomplish this is to have the material of the stent interact directly with the vessel. This can be achieved by better stent materials, or by impregnating the stent with drugs or genes to modify the vessel wall. This chapter will describe several such approaches under consideration.

Aggressive medulloblastoma with high-level N-myc amplification.

A 27-year-old man was treated for an aggressive cerebellar medulloblastoma that, at operation, exhibited dural invasion. Six months after gross total resection and radiation therapy, a "surgical metastasis" developed in the lower portion of the surgical scar. The tumor grew rapidly down into the right side of his neck. Chemotherapy failed, and he subsequently died. Cytogenetic and molecular genetic studies revealed multiple numeric and structural chromosome abnormalities, including an abnormal chromosome 17p arm, more than 100-fold N-myc amplification, a rearranged c-myc gene, and a 16-base pair deletion involving exon 7 of the p53 gene. We postulate that these genetic features may have contributed to the aggressive behavior of the tumor.

Phyllodes tumor: clinicopathologic review of 60 patients and flow cytometric analysis in 30 patients.

We reviewed 66 phyllodes tumors of the breast from 60 patients. Our patients included 59 women and one man ranging in age from 16 to 72 years. Fifty patients presented for primary treatment of newly diagnosed breast masses, nine presented with recurrent tumors, and one presented with soft tissue metastases 9 years after bilateral subcutaneous mastectomies and multiple chest wall recurrences of phyllodes tumor. After 0.3 to 53.2 years (mean, 15.5 years) of follow-up, 26 (43.3%) patients are free of disease without recurrence, 26 (43.3%) patients are dead of other (17 patients) or unknown (nine patients) causes, four (6.7%) patients had locally recurrent tumor 0.7 to 2.9 years after lumpectomy and are free of disease 3 months to 12 years after re-excision or simple mastectomy, two (3.3%) patients are lost to follow-up, and two (3.3%) patients died with metastatic disease 1.8 and 7 years after diagnosis. Histologic features and flow cytometric analysis showed no correlation with outcome. Fifty-six breast tumors were biphasic and nine were purely stromal tumors. Twenty-six (47%) biphasic tumors showed stromal overgrowth. Tumor margins were pushing in 20 (39%) and infiltrative in 29 (61%) of 49 evaluable cases. Twenty-one tumors were highly cellular and 17 showed cytologic atypia. Necrosis was identified in 16 tumors. Mitotic rates ranged from 0/10 high-power fields to 48/10 high-power fields. Twenty-four diploid, six aneuploid, three tetraploid, and one polyploid tumor were identified by flow cytometry. S-phase fractions tended to be higher in nondiploid tumors. Neither DNA content nor S-phase fraction correlated with outcome. Our results indicate that most mammary phyllodes tumors, including purely stromal tumors, behave as low-grade, nonmetastasizing neoplasms. Neither histologic evaluation nor DNA content provides reliable clues concerning the natural history of an individual tumor.

Clinical experience with aztreonam in urinary and respiratory tract infections.

Twenty patients with severe infection, 10 of the urinary tract and the other 10 of the respiratory tract, were enrolled in a clinical trial of aztreonam, a new monobactam antimicrobial agent. For the urinary tract infections, the mean duration of treatment was 7 days, with doses ranging from 0.25 to 1.0 g aztreonam intravenously twice daily. Sustained clinical and microbiological cure was achieved in 9 of the 10 patients. In the group with respiratory infections, the mean duration of treatment was 9.3 days, patients receiving 1 g aztreonam intravenously 3-times daily. Initial clinical cure was achieved in 9 of the patients, the tenth showing an incomplete response. However, bacteriological recurrence, related to the persistent nature of the underlying disease, occurred in 6 of the 10 patients during the 1-month follow-up period. The only side-effects were mild, transient biochemical abnormalities which did not require drug withdrawal in any patient.