Disruption of the myocardial extracellular matrix leads to cardiac dysfunction.

MMP activity with disruption of structural collagen has been implicated in the pathophysiology of dilated cardiomyopathy. To examine the role of this enzyme in cardiac function, a transgenic mouse was created that constitutively expressed human collagenase (MMP-1) in the heart. At 6 months of age, these animals demonstrated compensatory myocyte hypertrophy with an increase in the cardiac collagen concentration due to elevated transcription of type III collagen. Chronic myocardial expression of MMP-1 produced loss of cardiac interstitial collagen coincident with a marked deterioration of systolic and diastolic function at 12 months of age. This is the first animal model demonstrating that direct disruption of the extracellular matrix in the heart reproduces the changes observed in the progression of human heart failure.

Rapid in vivo monitoring of chemotherapeutic response using weighted sodium magnetic resonance imaging.

A novel pulse sequence strategy uses sodium magnetic resonance imaging to monitor the response to chemotherapy of mouse xenograft tumors propagated from human prostate cancer cell lines. An inversion pulse suppresses sodium with long longitudinal relaxation times, weighting the image toward intracellular sodium nuclei. Comparing these weighted sodium images before and 24 h after administration of antineoplastics, we measured a 36 +/- 4% (P < 0.001; n = 16) increase in signal intensity. Experiments with these same drugs and cells, treated in culture, detected a significant intracellular sodium elevation (10-20 mM) using a ratiometric fluorescent dye. Flow cytometry studies showed that this elevation preceded cell death by apoptosis, as determined by fluorescent end-labeling of apoptotic nuclei or Annexin V binding. Histopathology on formalin-fixed sections of explanted tumors confirmed that drug administration reduces proliferation (2.2 versus 8.6 mitotic figures per high power field; P < 0.0001), an effect that inversely correlates with the sodium magnetic resonance image response on a tumor-to-tumor basis (P < 0.02; n = 10). Morphological features, such as central zones of nonviable cells, rims of active apoptosis, and areas of viable tumor, could be distinguished by comparing weighted and unweighted images. Advantages of this sodium imaging technique include rapid determination of drug efficacy, improved diagnosis of lesions, ease of coregistration with high resolution proton magnetic resonance imaging, and absence of costly or toxic reagents.

Potential cost-effectiveness of public access defibrillation in the United States.

BACKGROUND: Approximately 360,000 Americans experience sudden cardiac arrest each year; current treatments are expensive and not very effective. Public access defibrillation (PAD) is a novel treatment for out-of-hospital sudden cardiac arrest that refers to use of automated external defibrillators by the lay public or by nonmedical personnel such as police. A clinical trial has been proposed to evaluate the effectiveness of public access defibrillation, but it is unclear whether such early defibrillation will offer sufficient value for money. Our objective was to estimate the potential cost-effectiveness of public access defibrillation by use of decision analysis. METHODS AND RESULTS: A decision model compared the potential cost-effectiveness of standard emergency medical services (EMS) systems with that of EMS supplemented by PAD. We considered defibrillation by lay responders or police, using an analysis with a US health-care perspective. Input data were derived from published data or fiscal databases. Future costs and effects were discounted at 3%. Monte Carlo simulation was performed to estimate the variability in the costs and effects of each program. Sensitivity analyses assessed the robustness of the results to changes in input data. A standard EMS system had a median cost of $5900 per cardiac arrest patient (interquartile range, IQR, $3200 to $10,900) and yielded a median of 0.25 quality-adjusted life years (IQR, 0.20 to 0.30). PAD by lay responders had a median incremental cost of $44,000 per additional quality-adjusted life year (IQR, $29,000 to $68,900). PAD by police had a median incremental cost of $27,200 per additional quality-adjusted life year (IQR, $15,700 to $47,800). The results were sensitive to changes in the cost and relative survival benefit of PAD. CONCLUSIONS: Although more expensive than standard EMS for sudden cardiac arrest, PAD may be economically attractive. The effectiveness and cost-effectiveness of PAD should be assessed in a randomized, controlled trial.

Compensation to a department of medicine and its faculty members for the teaching of medical students and house staff.

BACKGROUND: Changes in the organization and financing of health care threaten to alter the prevailing system of financing the teaching of medical students and residents. Little information is available from private medical schools and teaching hospitals about the extent of teaching by faculty members or the mechanisms and levels of reimbursement for teaching. METHODS: We surveyed faculty members in the Department of Medicine at Columbia-Presbyterian Medical Center to ascertain the extent of their teaching activities. A standard number of hours was assigned to each activity, and the total number of teaching hours was calculated for each faculty member. Teaching of fellows and in continuing medical education programs was excluded. We also determined how much money the Department of Medicine received in payment for faculty members' teaching activities, and the sources of this compensation. RESULTS: In the 1992-1993 academic year, the 188 full-time faculty members spent a total of 46,086 hours teaching (mean [+/- SD], 245 +/- 178 hours per faculty member); 10,780 hours (23.4 percent) were spent teaching medical students, and 35,306 hours (76.6 percent) teaching house staff. Eighty percent of faculty members taught for 137 or more hours each. In a multivariate analysis including faculty rank, subspecialty division, years since graduation from medical school, sex, and tenure or clinical track, senior faculty members (P = 0.02), members of certain subspecialty divisions (P < 0.001), and women (P = 0.05) contributed more than the average number of teaching hours. An additional 56 non-full-time faculty members contributed a total of 5684 hours. The net reimbursement to the department for teaching totaled $965,808, or about $16 per hour of teaching by full-time faculty members, after the cost of fringe benefits was excluded. CONCLUSIONS: Faculty members of the department of medicine at a major medical center contribute a large number of hours teaching medical students and house staff. This effort is poorly compensated. Cost-containment efforts have the potential to jeopardize fragile social contracts at academic health centers whereby the faculty participates in teaching by contributing unreimbursed or underreimbursed time.

Observations of ventilation during resuscitation in a canine model.

BACKGROUND: Fear of infection limits the willingness of laymen to do cardiopulmonary resuscitation (CPR). This study assessed the time course of change in arterial blood gases during resuscitation with only chest compression (no ventilation) in an effort to identify the time for which ventilation could be deferred. METHODS AND RESULTS: Aortic pressures and arterial blood gases were monitored in seven 20- to 30-kg dogs in ventricular fibrillation (VF) at 2-minute intervals during chest compression alone (no ventilation) at 80 to 100 compressions per minute. Before the induction of ventricular fibrillation, all animals were intubated and ventilated with room air, 10 mL/kg. The endotracheal tube was removed when VF was induced. Pre-VF arterial pH, PCO2, and O2 saturation were (mean +/- SEM) 7.39 +/- 0.02, 27.0 +/- 1.5 mm Hg, and 97.5 +/- 0.5%, respectively, with aortic pressures being 143.2 +/- 5.7/116.2 +/- 4.6 mm Hg. At 4 minutes of chest compression alone, the corresponding values were 7.39 +/- 0.03, 24.3 +/- 3.1 mm Hg, and 93.9 +/- 3.0%, with an arterial pressure of 48.1 +/- 7.7/22.6 +/- 3.9 mm Hg. Mean minute ventilation during the fourth minute of CPR, measured with a face mask-pneumotachometer, was 5.2 +/- 1.1 L/min. CONCLUSIONS: These data suggest that in the dog model of witnessed arrest, chest compression alone during CPR can maintain adequate gas exchange to sustain O2 saturation > 90% for > 4 minutes. The need for immediate ventilation during witnessed arrest should be reexamined.

Rotational deformation of the canine left ventricle measured by magnetic resonance tagging: effects of catecholamines, ischaemia, and pacing.

OBJECTIVE: The aim was to investigate the generation of rotation of the left ventricular apex with respect to the base by magnetic resonance tagging, a non-invasive method of labelling the myocardium, in a canine model. METHODS: 18 dogs were imaged at baseline and during: (1) inotropic stimulation with dobutamine; (2) chronotropic stimulation with atrial pacing; (3) anterior wall ischaemia; (4) posterior wall ischaemia; and (5) varying left ventricular activation site; six dogs underwent each intervention. Apical rotation of the apex (torsion) was quantified. The epicardium and the endocardium were considered separately, as were the anterior and posterior walls. RESULTS: Mean torsion of the epicardium [anterior 3.1(SEM 1.2) degrees, posterior 9.9(1.0) degrees] was less than that of the endocardium [anterior 8.1(2.6) degrees, posterior 14.9(2.0) degrees, p < 0.05 for both]. Anterior torsion was less than posterior torsion for both the epicardium, p < 0.05, and the endocardium, p < 0.05. Dobutamine increased torsion of both the epicardium [anterior 13.3(2.2) degrees, posterior 12.6(1.7) degrees, p < 0.05 for both] and the endocardium [anterior 24.6(2.3) degrees, posterior 16.5(2.1) degrees, p < 0.05 for both]. Atrial pacing at 160% baseline rate increased torsion of both the anterior wall [epicardium 6.6(1.0) degrees, endocardium 11.3(1.2) degrees, p < 0.05] and the posterior wall [epicardium 13.0(1.3) degrees, endocardium 19.4(1.9) degrees, p < 0.05]. Anterior wall ischaemia reduced torsion of the anterior wall only [epicardium -2.0(1.0) degrees, endocardium 6.7(2.3) degrees, both p < 0.05]. Posterior wall ischaemia reduced torsion of the posterior wall of the epicardium only [7.1(1.2) degrees, p < 0.05] but also reduced torsion of the anterior wall [epicardium 0.7(1.0) degrees, endocardium 2.4(1.6) degrees, p < 0.05 for both]. Altering the pattern of left ventricular activation by atrioventricular pacing reduced torsion of the posterior wall of the epicardium [6.6(1.2) degrees, p < 0.05] and of the anterior [3.6(1.9) degrees, p < 0.05] and posterior [7.1(1.6) degrees, p < 0.05] walls of the endocardium. CONCLUSIONS: Rotational deformation of the left ventricle is dependent on the pattern of left ventricular activation and the contractile state. That a decrease in the contractile state in one area (by ischaemia) can cause a decrease in rotation in another suggests that this rotation depends on the complex fiber arrangement of the whole ventricle.

Hemodynamic vascular forces contribute to impaired endothelium-dependent vasodilation in reperfused canine epicardial coronary arteries.

OBJECTIVES: We studied canine coronary arterial vasoreactivity after occlusion and reperfusion to examine whether reduced flow or pressure contributed to the abnormalities observed. BACKGROUND: Ischemia and reperfusion alter endothelial and myocardial function. Causative factors may include altered flow, complement activation or free radical production by endothelial or white blood cells after reoxygenation and neutrophil activation. METHODS: The coronary arteries of anesthetized, open chest dogs were subjected to 90-min occlusion +/- 2 h of reperfusion. The effect of reperfusion on arterial responses to intracoronary acetylcholine, nitroprusside and phenylephrine was studied using in vivo ultrasound. Arterial segments were also harvested, perfused ex vivo with cell-free buffer and exposed to potassium chloride, nitroprusside, acetylcholine and bradykinin. The effect of ex vivo flow cessation with or without maintained intralumen pressure was also studied. RESULTS: Results are expressed as mean value +/- SEM. In vivo arterial cross-sectional area increased during infusion with acetylcholine (10(-5) mol/liter [18.5 +/- 9%]) and nitroprusside (10(-5) mol/liter [22.5 +/- 10%]) and decreased with phenylephrine (10(-5) mol/liter [7.6 +/- 7%]). After reperfusion, acetylcholine caused 13.5 +/- 9% vasoconstriction. Nitroprusside and phenylephrine responses were unchanged. Reperfused arterial segments also showed impaired vasodilation in response to 10(-6) mol/liter of acetylcholine (10.6 +/- 5.1% vs. 47.1 +/- 4.9% in control vessels) and 10(-8) mol/liter of bradykinin (4.4 +/- 6.7% vs. 27.9 +/- 8% in control vessels). Ex vivo flow cessation impaired acetylcholine-mediated vasodilation, but this abnormality was prevented when high intralumen pressure was maintained during the no-flow period. CONCLUSIONS: Reduction in flow and intralumen pressure contribute to the impaired acetylcholine-mediated vasodilation seen after coronary occlusion. This is prevented by maintaining high intralumen pressure during the no-flow period, suggesting that hemodynamic forces may change endothelial function independent of circulating complement or blood cell elements.

Relation of regional cross-fiber shortening to wall thickening in the intact heart. Three-dimensional strain analysis by NMR tagging.

BACKGROUND: The mechanism by which small amounts of myofiber shortening lead to extensive wall thickening is unknown. When isolated fibers shorten, they thicken in the two orthogonal directions. In situ fibers, however, vary in their orientation through the wall, and each is tethered to near or distant neighbors, which allows shortening to occur both in the direction of the fibers and also perpendicular to them. This "cross-fiber" shortening may enable the wall to shorten in two directions and thereby thicken extensively in the third. METHODS AND RESULTS: Nuclear magnetic resonance tagging is a noninvasive method of labeling and tracking myocardium of the entire heart in three dimensions that does not interfere with myocardial motion. To investigate the presence and importance of cross-fiber shortening in the intact left ventricle, 10 closed-chest dogs were studied by nuclear magnetic resonance tagging. Five short-axis and four long-axis images were acquired to reconstruct 32 cubes of myocardium in each dog at end diastole and end systole. Pathological dissection was performed to determine the fiber direction at the epicardium, midwall, and endocardium of each cube. Strain was computed from the three-dimensional cube coordinates in the fiber and cross-fiber directions for epicardial and endocardial surfaces, and thickening of the full wall and its epicardial and endocardial halves was determined. Shear deformations were also calculated. Fiber strain at the epicardium and endocardium was -6.4 +/- 0.7% and -8.5 +/- 0.6% (mean +/- SEM), respectively (difference, P > .05). Cross-fiber strain at epicardium and endocardium was -0.6 +/- 0.5% and -25 +/- 0.6%, respectively (difference, P < .05). Thickening of the full wall reached 32.5 +/- 1.0%, composed of epicardial thickening of 25.5 +/- 0.6% and endocardial thickening of 43.3 +/- 1.0% (difference, P < .05). Fiber/cross-fiber shear strain was small (< 3%). Significant regional differences were present in all strains. A significant correlation was found between the extents of regional thickening and cross-fiber shortening. CONCLUSIONS: Cross-fiber shortening at the endocardium, therefore, far exceeds cross-fiber shortening at the epicardium and fiber shortening at both epicardium and endocardium. Since no active shortening can occur locally in the cross-fiber direction, the extensive endocardial cross-fiber shortening must result from interaction with differently aligned fibers at a distance. The correlation between regional thickening and cross-fiber shortening supports the hypothesis that this interaction is the mechanism for amplifying small amounts of fiber shortening to cause extensive endocardial thickening.

Soluble complement receptor type 1 inhibits the complement pathway and prevents contractile failure in the postischemic heart. Evidence that complement activation is required for neutrophil-mediated reperfusion injury.

BACKGROUND: Complement-mediated neutrophil activation has been hypothesized to be an important mechanism of reperfusion injury. It has been proposed that soluble complement receptor 1 (sCR1), a potent inhibitor of both classical and alternative complement pathways, may prevent the complement-dependent activation of polymorphonuclear leukocytes (PMNs) that occurs within postischemic myocardium and thereby inhibit PMN-derived free radical generation and prevent postischemic contractile failure. Therefore, we performed studies to determine the effects of sCR1 on contractile function, PMN adhesion, complement deposition, and PMN-derived free radical generation in the postischemic heart. METHODS AND RESULTS: Studies were performed in an isolated rat heart model in which the isolated effects of given cellular or humoral factors could be determined. Plasma and PMNs were present to study the effects of sCR1 on contractile function, coronary flow, leukocyte adhesion, complement deposition, and PMN-derived free radical generation. Isolated rat hearts were perfused by the method of Langendorff (n = 10 in each group) and subjected to 20 minutes of global ischemia and reperfusion with PMNs and plasma in the presence or absence of sCR1. Left ventricular developed pressure (LVDP), coronary flow (CF), left ventricular end-diastolic pressure (LVEDP), and rate-pressure product (RPP) were measured during the preischemic period, during 1-minute control infusion of PMNs and plasma, and on reflow following 20 minutes of global ischemia. During the preischemic control infusion, no significant alterations in the physiologic parameters were observed, and there was no measurable free radical generation. Reperfusion with sCR1 markedly improved the recovery of postischemic contractile function. LVDP after 45 minutes of reperfusion was 76 +/- 9.8% compared with 32 +/- 6.2% (P < .001). In addition, significant improvements in LVEDP, RPP, and CF were observed in hearts treated with sCR1. Additional experiments were also performed to determine the effect of sCR1 on complement-mediated PMN activation. Measurements of PMN-derived free radical generation were performed in both isolated PMNs and the coronary effluent of hearts using electron paramagnetic resonance spectroscopy (EPR) with the spin trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). EPR measurements in both isolated PMNs and coronary effluent demonstrated that sCR1 blocked complement-mediated free radical generation from the PMNs. Increased accumulation of PMNs was observed both in hearts treated with sCR1 and in those not treated with sCR1. Immunohistochemical staining of the postischemic myocardial tissue demonstrated marked complement deposition on the endothelial surface of small arterioles and capillaries, which was prevented by sCR1 treatment. Thus, sCR1 did not prevent PMN adhesion but did prevent complement deposition with activation of the PMN oxidative burst. CONCLUSIONS: The potent complement inhibitor sCR1 was found to be effective at preventing postischemic myocardial contractile dysfunction and enhancing the recovery of coronary flow. This study demonstrated that complement activation occurs in postischemic myocardium and is necessary for activation of the neutrophil oxidative burst with the generation of reactive oxygen free radicals. The process of neutrophil adhesion, however, was not affected by sCR1 and was independent of complement factors. These findings demonstrate the sCR1 is a highly potent agent at preventing complement-mediated PMN activation and secondary free radical generation in the postischemic heart. This genetically engineered protein appears to be a promising therapeutic agent in the prevention of myocardial reperfusion injury.