Marlina M. Multani

Cardiopulmonary bypass induces the synthesis and release of matrix metalloproteinases

BACKGROUND A number of cellular and molecular events can be induced after cardiac procedures requiring cardiopulmonary bypass (CPB). The matrix metalloproteinases (MMPs) are a recently discovered family of enzymes that degrade the extracellular matrix, but expression during and after CPB is unknown. METHODS Systemic plasma MMP levels were measured in patients (n = 28, 63 +/- 1 years) undergoing elective coronary revascularization requiring CPB at baseline, termination of CPB, and 30 minutes, 6 and 24 hours after CPB. Representative classes of MMP species known to degrade matrix and basement membrane components were selected for study. Specifically, the interstitial collagenases MMP-8 and MMP-13, and the gelatinases MMP-2 and MMP-9 were determined by internally validated enzyme-linked immunosorbent assay. RESULTS The MMP-8 levels increased by fourfold at separation from CPB, and returned to within normal values within 30 minutes after CPB. The proenzyme forms of MMP-13 and MMP-9 increased by more than twofold at cross-clamp release and returned within normal limits within 6 hours after CPB. The proform of MMP-2 increased from baseline values at 6 and 24 hours postoperatively; likely indicative of de novo synthesis. CONCLUSIONS A specific portfolio of MMPs are released and synthesized during and after CPB. Because MMPs can degrade extracellular proteins essential for maintaining normal cellular architecture and function, enhanced MMP release and activation may contribute to alterations in tissue homeostasis in the early postoperative period.

Differential effects of calcium channel antagonists in the amelioration of radial artery vasospasm

BACKGROUND Radial artery (RA) is being used for coronary artery bypass grafting (CABG) with greater frequency. However, RA is prone to post-CABG vasospasm, which may be neurohormonally mediated. Use of the calcium channel antagonist diltiazem has been advocated as a strategy to reduce post-CABG RA vasospasm. However, whether and to what degree different calcium channel antagonists influence neurohormonally induced RA vasoconstriction remains unknown. METHODS RA segments were collected from patients undergoing elective CABG (n = 13), and isometric tension was examined in the presence of endothelin (10 nM) or norepinephrine (1 microM). In matched RA, endothelin- or norepinephrine-induced contractions were measured in the presence of diltiazem (277 nM), amlodipine (73 nM), or nifedipine (145 nM). These concentrations of calcium channel antagonists were based upon clinical plasma profiles. RESULTS Endothelin and norepinephrine caused a significant increase in RA-developed tension (0.54+/-0.1 and 0.68+/-0.1 g/mg, respectively; p<0.05). Amlodipine or nifedipine significantly reduced RA vasoconstriction in the presence of endothelin (30+/-6% and 41+/-9%, respectively; p<0.05) or norepinephrine (27+/-8% and 53+/-9%, respectively; p<0.05), whereas diltiazem did not significantly reduce RA vasoconstriction. CONCLUSIONS These results demonstrate that neurohormonal factors released post-CABG can cause RA vasoconstriction, and that calcium channel antagonists are not equally effective in abrogating that response. Both amlodipine and nifedipine, which have a higher degree of vascular selectivity, appear to be the most effective in reducing RA vasoconstriction.

Release of matrix metalloproteinases following alcohol septal ablation in hypertrophic obstructive cardiomyopathy

OBJECTIVES This study examined plasma levels of certain matrix metalloproteinase (MMP) and tissue inhibitor of matrix metalloproteinase (TIMP) species before and after alcohol-induced myocardial infarction (MI) in patients with hypertrophic obstructive cardiomyopathy (HOCM). BACKGROUND Matrix metalloproteinases contribute to tissue remodeling, and endogenous control of MMP activity is achieved by the concordant release and binding of TIMPs. Animal models of MI have demonstrated a role for MMP activation in myocardial remodeling. However, the temporal relationship of MMP and TIMP release following a controlled myocardial injury in humans remains unknown. METHODS Plasma levels for the gelatinases MMP-2 and MMP-9, and for the collagenases MMP-8 and MMP-13, as well as TIMP-1 profiles were examined (by enzyme-linked immunosorbent assay) at baseline and serially up to 60 h following alcohol injection into the septal perforator artery in order to induce an MI in 51 patients with HOCM (age 55 +/- 2 years). RESULTS Plasma creatine kinase (MB isoform), indicating myocardial injury, increased 2,150% 18 h post-MI (p < 0.05). Plasma MMP-9 increased by over 400% and MMP-8 by over 100% from baseline values by 12 h post-MI (p < 0.05 vs. baseline). A similar temporal profile was not observed for MMP-2 and MMP-13. In addition, a concomitant increase in plasma TIMP-1 levels did not occur post-MI. As a result, MMP/TIMP stoichiometry (MMP-9/TIMP-1 ratio) increased significantly post-MI, suggestive of reduced TIMP-1 mediated MMP-9 inhibition, which would potentially enhance extracellular myocardial remodeling. CONCLUSIONS These unique results demonstrated that induction of a controlled myocardial injury in humans, specifically through alcohol-induced MI, caused species- and time-dependent perturbations of MMP/TIMP stoichiometry that would facilitate myocardial remodeling in the early post-MI setting.

Effects of Adrenomedullin on Human Myocyte Contractile Function and β-Adrenergic Response

Background: Adrenomedullin has been demonstrated to cause systemic vasodilation, and increased plasma adrenomedullin levels have been observed in cardiovascular disease states such as heart failure. While adrenomedullin receptors have been localized to the myocardium, the effects of adrenomedullin on human myocyte contractility remained unknown. Methods and Results: Left ventricular myocytes were isolated from myocardial biopsies of patients (n = 16) undergoing elective coronary artery bypass surgery with normal left ventricular ejection fractions (51 ± 1%). A total of 233 left ventricular myocytes were studied by videomicroscopy. Myocyte shortening velocity (,um/s) was measured at baseline and following the addition of either 3 nM, 30 nM, or 60 nM of adrenomedullin. The change in myocyte shortening velocity with increasing concentrations of adrenomedullin was computed. At all concentrations, adrenomedullin reduced myocyte shortening velocity from baseline values (P < 0.05). Next, the potential interaction of adrenomedullin with the P-adrenergic receptor system was examined using 25 nM isoproterenol. The 3-adrenergic receptor-mediated increase in the myocyte shortening velocity was blunted with adrenomedullin (29 ± 7 vs 63 ± 13 tm/s, P < 0.05). Conclusions: These unique findings demonstrate that adrenomedullin reduced contractility in isolated human left ventricular myocytes and exhibited a negative interaction with the fadrenergic receptor system. Past studies have shown that adrenomedullin induces nitric oxide synthesis and that nitric oxide can uncouple myocyte metabolism. Thus, while adrenomedullin causes systemic vasodilation, this peptide can also exert a negative contractile effect in human left ventricular myocytes.

Individualized outcome feedback produces voluntary antiemetic prescribing practice changes

STUDY OBJECTIVE To determine the impact of individualized outcome feedback on antiemetic prescribing practices and compare outcomes of a cost-effective, standardized antiemetic protocol (PROT) to that of customized antiemetic therapy (NONPROT). DESIGN Prospective, observational study with randomized component. SETTING Postanesthesia care unit (PACU) of an academic medical center. PATIENTS 3027 consecutive ASA physical status I, II, and III patients receiving general anesthesia. INTERVENTIONS Patients were randomized to receive 0.625 mg droperidol or 4 mg ondansetron for postoperative nausea and/or vomiting (PONV) from a protocol, or received customized antiemetic therapy. MEASUREMENTS AND MAIN RESULTS Incidence of PACU PONV, selection of PROT versus NONPROT, patient satisfaction, and use of PONV prophylaxis were measured and indexed by an attending anesthesiologist in a monthly report for 4 months. Monthly expenditures for antiemetic therapy prior to, during, and after the study were collected. Literature on PONV outcomes, appropriate timing, and selection of PONV prophylaxis was distributed. The NONPROT group was slightly older than the PROT group; otherwise, demographics were similar between all groups. The incidence of PONV did not differ between the PROT and NONPROT groups (11% vs. 10%), and the incidence of PONV in patients receiving prophylaxis was higher in both groups (17% PROT vs. 15% NONPROT). Patients receiving ondansetron as a first-line drug required rescue therapy less often (5%) than those receiving droperidol (14%); however, patient satisfaction was indistinguishable among all groups. During the study, the use of prophylaxis decreased 47% without an increase in PONV, and PROT selection increased 54%. CONCLUSIONS Individualized outcome feedback produced a 48% reduction in monthly expenditures for ondansetron and droperidol, which was sustained after the study. Patients satisfaction between ondansetron 4 mg and droperidol 0.625 mg given in the PACU did not differ in spite of a slightly greater efficacy of ondansetron as a first-line drug.

Myocardial Bradykinin Following Acute Angiotensin-Converting Enzyme Inhibition, AT1 Receptor Blockade, or Combined Inhibition in Congestive Heart Failure

Background: The present study examined the effects of acute angiotensin-converting enzyme inhibition (ACEI), AT, receptor blockade (AT, block), or combined treatment on in vitro and in vivo bradykinin (BK) levels. Methods: BK levels were measured in isolated porcine myocyte preparations (n = 13) in the presence of exogenous BK (10-8 M); with an ACEI (benezaprilat; 0.1 mM) and BK; an AT, block (valsartan; 10-5 M) and BK; and combined treatment and BK. In a second study, myocardial microdialysis was used to measure porcine interstitial BK levels in both normal (n = 14) and pacing-induced congestive heart failure (CHF) (240 beats/min, 3 weeks, n = 16) under the following conditions: baseline, following ACEI (benezaprilat, 0.0625 mg/kg) or AT, block (valsartan, 0. I mg/kg), and a combined treatment (benezaprilat, 0.0625 mg/kg; valsartan, 0.1 mg/kg). Results: In the left ventricular myocyte study, BK levels increased over 93% with all treatments compared to untreated values (P < 0.05). In the in vivo study, basal interstitial BK values were lower in the CHF group than in controls (2.64 ± 0.57 vs 5.91 + 1.4 nM, respectively, P < 0.05). Following acute infusion of the ACEI, BK levels in the CHF state increased from baseline (57% ± 22; P < 0.05). Following combined ACEIIAT, block, BK levels increased from baseline in both control (42% ± 11) and CHF groups (60% ± 22; P < 0.05 for both). Conclusion: These findings suggest that ACEI, or combined ACEI/AT, block increased BK at the level of the myocyte and potentiated BK levels in the CHF myocardial interstitium.