Florence H. Sheehan

The effect of blockade of the CD11/CD18 integrin receptor on infarct size in patients with acute myocardial infarction treated with direct angioplasty: The results of the HALT-MI study

OBJECTIVE The purpose of this study was to determine whether Hu23F2G (LeukoArrest), an antibody to the CD11/CD18 integrin receptors, would reduce infarct size in patients undergoing primary angioplasty for an acute myocardial infarction. BACKGROUND Reperfusion injury in acute myocardial infarction has been shown experimentally to be related to neutrophil accumulation. Inhibitors of the CD11/CD18 or CD18 integrin receptors have been shown to reduce infarct size in experimental models. METHODS Patients within 6 h of onset of chest pain with ST-segment elevation were randomized to receive either 0.3 mg/kg or 1.0 mg/kg of Hu23F2G or placebo just before angioplasty of occluded arteries (Thrombolysis in Myocardial Infarction TIMI flow grade 0 or 1). The primary end point was infarct size as measured by sestamibi single-photon emission computed tomography (SPECT) scan five to nine days later. RESULTS Four-hundred and twenty patients were enrolled and received a placebo or the study drug. The groups did not differ in baseline or angiographic characteristics or angioplasty results. Infarct size was 16%, 17.2% and 16.6%, for placebo, 0.3 mg/kg and 1.0 mg/kg, respectively, of the left ventricle (p = NS). No differences were evident in those patients with anterior myocardial infarction or those presenting within 2 h of onset of chest pain. Corrected TIMI frame count was also not different between groups. Clinical events at 30 days were very low, with a mortality of 0.8%, 1.4% and 3.3%, respectively. The drug was well tolerated, with a slight increase in minor infections in the high dose group. CONCLUSIONS The results of this multicenter, double-blind, placebo-controlled, randomized clinical trial demonstrated that an antibody to CD11/CD18 leukocyte integrin receptor did not reduce infarct size in patients who underwent primary angioplasty.

The Western Washington Intravenous Streptokinase in Acute Myocardial Infarction Randomized Trial.

Three hundred sixty-eight patients were randomly assigned to receive intravenous streptokinase (IVSK) (n = 191) or standard therapy (n = 177) to determine the efficacy of IVSK in the treatment of acute myocardial infarction. The mean time to treatment was 3.5 hr. At 14 days there were 12 deaths in the treatment group (6.3%) and 17 deaths in the control group (9.6%) (p = .23). Early mortality was related to infarct location. Fourteen day mortality for anterior infarctions was 10.4% for treatment with IVSK and 22.4% for control patients (p = .06) and was similar for IVSK-treated patients with inferior infarctions, 4.0% vs 1.8% (p = .32). For those randomized under 3 hr, 14 day mortality tends to be lower in treated patients, 5.2% vs 11.5% (p = .11). There was significant improvement in long-term survival for patients with anterior infarction; 2 year survival was 81% for IVSK-treated patients and 65% for control patients (p = .05). There was no improvement in survival for patients with inferior myocardial infarction (p = .27). We conclude that patients with anterior myocardial infarction have improved survival when treated within the first 6 hr of symptoms. Patients with inferior infarction do not appear to have improved survival with thrombolytic therapy. Some of this improvement in survival in patients with anterior infarction may be due to a higher frequency of revascularization procedures in the treatment group.

Effect of interventions in salvaging left ventricular function in acute myocardial infarction: A study of intracoronary streptokinase

The ability of intracoronary streptokinase (STK) infused early in acute myocardial infarction (MI) to salvage left ventricular (LV) function was studied in 52 patients who underwent contrast angiography immediately after STK and 6 +/- 7 weeks later. Ten nonrevascularized patients had no lysis or reocclusion. Of 42 patients with thrombolysis, 22 with optimal reperfusion underwent coronary artery bypass grafting (CABG) to prevent rethrombosis (STK + CABG group) and 20 did not (STK group). Motion was measured at 100 chords around the left ventricle and expressed in standard deviations (SD) from the normal mean. Hypokinesia was computed as the mean motion of chords in the infarct artery territory and hyperkinesia on the opposite wall was similarly computed. Hypokinesia improved greater than or equal to 1 SD/chord in 9 STK + CABG patients (41%), 8 STK patients (30%) (p = not significant versus STK + CABG) and 0 nonrevascularized patients. However, the ejection fraction did not change because it was normal in acute MI despite severe hypokinesia due to hyperkinesia on the opposite wall, and a subsequent decrease in hyperkinesia masked significant improvement in hypokinesia. It is concluded that regional wall motion must be measured to adequately assess the effect of therapeutic interventions on LV function. Early thrombolysis in acute MI results in improved LV function. The main benefit of CABG is to prevent rethrombosis.

Cardioprotective Effects of the Na+/H+ Exchange Inhibitor Cariporide in Patients With Acute Anterior Myocardial Infarction Undergoing Direct PTCA

BACKGROUND Activation of Na(+)/H(+) exchange in myocardial ischemia and/or reperfusion leads to calcium overload and myocardial injury. Experimental studies have shown that Na(+)/H(+) exchange inhibitors can attenuate Ca(2+) influx into cardiomyocytes. We therefore performed a multicenter, randomized, placebo-controlled clinical trial to test the hypothesis that inhibition of Na(+)/H(+) exchange limits infarct size and improves myocardial function in patients with acute anterior myocardial infarction (MI) treated with direct PTCA. METHODS AND RESULTS One hundred patients were randomized to receive placebo (n=51) or a 40-mg intravenous bolus of the Na(+)/H(+) exchange inhibitor cariporide (HOE 642) (n=49) before reperfusion. Global and regional left ventricular functions were analyzed by use of paired contrast left ventriculograms performed before and 21 days after PTCA and myocardial enzymes (ie, creatine kinase ¿CK, CK-MB, and LDH) as markers for myocardial tissue injury were evaluated. At follow-up, the ejection fraction was higher (50% versus 40%; P<0.05) and the end-systolic volume was lower (69.0 versus 97.0 mL; P<0.05) in the cariporide group. Significant improvements in some indices of regional wall motion abnormalities were observed, such as the percentage of chords with hypokinesis < -2 SD (P=0.045) and the severity of hypokinesis in the border zone of the infarct region (P=0.052). In addition, CK, CK-MB, or LDH release was significantly reduced in the cariporide patients. CONCLUSIONS Our findings suggest that inhibition of Na(+)/H(+) exchange by cariporide may attenuate reperfusion injury and thereby improve the recovery from left ventricular dysfunction after MI.

Three-dimensional echocardiographic assessment of annular shape changes in the normal and regurgitant mitral valve

OBJECTIVES To compare mitral annular shape and motion throughout the cardiac cycle in patients with normal hearts versus those with functional mitral regurgitation (FMR). BACKGROUND The causes of mitral regurgitation without valvular disease are unclear, but the condition is associated with changes in annular shape and dynamics. Three-dimensional (3D) imaging provides a more comprehensive view of annular structure and allows accurate reconstructions at high spatial and temporal resolution. METHODS Nine normal subjects and 8 patients with FMR undergoing surgery underwent rotationally scanned transesophageal echocardiography. At every video frame of 1 sinus beat, the mitral annulus was manually traced and reconstructed in 3D by Fourier series. Annular projected area, nonplanarity, eccentricity, perimeter length, and interpeak and intervalley spans were determined at 10 time points in systole and 10 points in diastole. RESULTS The mitral annulus in patients with FMR had a larger area, perimeter, and interpeak span than in normal subjects (P <.001 for all). At mid-systole in normal annuli, area and perimeter reach a minimum, nonplanarity is greatest, and projected shape is least circular. These cyclic variations were not significant in patients with FMR. Annular area change closely paralleled perimeter change in all patients (mean r = 0.96 +/- 0.07). CONCLUSIONS FMR is associated with annular dilation and reduced cyclic variation in annular shape and area. Normal mitral valve function may depend on normal annular 3D shape and dimensions as well as annular plasticity. These observations may have implications for design and selection of mitral annular prostheses.

Early recovery of left ventricular function after thrombolytic therapy for acute myocardial infarction: an important determinant of survival

Thrombolytic therapy for acute myocardial infarction reduces early mortality, but full recovery of left ventricular function after reperfusion is delayed. Therefore, the relations among reperfusion, survival and the time course of left ventricular functional recovery were examined in 226 patients treated with intracoronary streptokinase; 77% (134 patients) had sustained reperfusion and 31 patients had no reperfusion or had reocclusion by day 3. Wall motion was measured from contrast ventriculograms performed in the acute period and 3 days later in the central and peripheral infarct regions and the noninfarct region by the centerline method in 165 patients. Patients with reperfusion had better survival (p less than 0.05, mean follow-up 4.5 years) and a higher ejection fraction at 3 days (52 +/- 12 versus 46 +/- 10%, p less than 0.02) attributable to a significantly different change in peripheral infarct region function between the acute and 3 day studies (0.1 +/- 1.0 versus -0.3 +/- 0.9 SD, p less than 0.05). These early functional changes were significant in patients with anterior myocardial infarction and showed similar trends in those with inferior myocardial infarction. On Cox regression analysis, function measured at 3 days was more predictive of survival than was function measured acutely (chi square for acute ejection fraction = 11.48 versus 24.59 at 3 days). Although, as previously reported, greater than 45% of total recovery of left ventricular function occurs later, the ejection fraction achieved by day 3 is already predictive of survival. Thus, the mechanism by which successful thrombolytic therapy enhances survival is improvement of regional and global left ventricular function early after acute myocardial infarction.

Intravenous urokinase in acute myocardial infarction

To achieve reperfusion early, an intravenous bolus of 2 million units of urokinase was administered in 50 patients with transmural acute myocardial infarction (AMI) 1.8 +/- 2.5 hours after the onset of symptoms. Coronary angiography performed 1.1 +/- 0.6 hours after urokinase therapy revealed patent coronary arteries in 30 patients (60%), with no significant difference between those with anterior and those with inferior AMI. Reocclusion occurred in only 1 of 24 patients restudied. Failure to achieve reperfusion was not related to the degree of systemic fibrinolytic activity, which was equally high in patients who did and those who did not achieve reperfusion, as evident from serially obtained fibrinogen measurements (77 +/- 52 vs 84 +/- 24 mg/dl, difference not significant). Plasmin activity, measured serially from 15 minutes to 24 hours after urokinase in 7 patients, was maximal at 15 minutes and undetectable after 3 hours. Wall motion at the infarct site measured from contrast ventriculograms was significantly better at follow-up only in patients in whom reperfusion was achieved and who received urokinase within 2 hours after the onset of symptoms as compared with patients in whom reperfusion was not achieved (-1.2 +/- 1.4 vs -2.4 +/- 0.9 standard deviations from normal, p less than 0.05). Peak serum creatine kinase level was significantly lower in patients in whom reperfusion was achieved than in those in whom it was not or those who had rethrombosis (802 +/- 763 vs 1,973 +/- 1,071 U/liter, p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Factors that determine recovery of left ventricular function after thrombolysis in patients with acute myocardial infarction.

The coronary and ventricular angiograms of 47 patients with acute myocardial infarction in whom reperfusion was achieved by intracoronary streptokinase were quantitatively analyzed to determine the factors that affect recovery of regional left ventricular function after reperfusion. Hypokinesis in the infarct region was measured by the centerline method and expressed in terms of standard deviations (SDs) from normal. Severity of coronary artery stenosis was measured quantitatively. Hypokinesis showed more significant improvement after thrombolysis in patients with minimum stenosis diameter of greater than 0.4 mm than in those with severe residual stenosis, i.e., stenosis producing a minimum diameter of 0.4 mm or less (1.0 +/- 1.3 SD/chord, n = 31, vs 0.0 +/- 0.9 SD/chord, n = 7; p less than .05). Improvement in hypokinesis was greater in patients who received thrombolytic therapy within 2 hr than in those treated later (2.1 +/- 1.1, n = 8, vs 0.7 +/- 1.0 SD/chord, n = 28; p less than .001). These results indicate that angiographic reperfusion alone may not be sufficient: reperfusion must provide adequate flow and be achieved early to salvage myocardial function.

Myocyte degeneration and cell death in hibernating human myocardium

OBJECTIVES The aim of this study was to analyze the morphologic characteristics of myocyte degeneration leading to replacement fibrosis in hibernating myocardium by use of electron microscopy and immunohistochemical techniques. BACKGROUND Data on the ultrastructure and the cytoskeleton of cardiomyocytes in myocardial hibernation are scarce. Incomplete or delayed functional recovery might be due to variable degree of cardiomyocyte degeneration in hibernating myocardium. METHODS In 24 patients, regional wall motion abnormalities were analyzed by use of the centerline method before and 6 +/- 1 months after coronary artery bypass surgery. Preoperative technetium-99m sestamibi uptake was measured by single-photon emission computed tomography for assessing regional perfusion. Fluorine-18 fluorodeoxyglucose uptake was measured by positron emission tomography to assess glucose metabolism. Transmural biopsy specimens were taken during coronary artery bypass surgery from the center of the hypocontractile area of the anterior wall. RESULTS The myocytes showed varying signs of mild-to-severe degenerative changes and an increased degree of fibrosis. Immunohistochemical analysis demonstrated disruption of the cytoskeletal proteins titin and alpha-actinin. Electron microscopy of the cell organelles and immunohistochemical analysis of the cytoskeleton showed a similarity in the degree of degenerative alterations. Group 1 (n = 11) represented patients with only minor structural alterations, whereas group 2 (n = 13) showed severe morphologic degenerative changes. Wall motion abnormalities showed postoperative improvements, and nuclear imaging revealed a perfusion-metabolism mismatch without significant differences between the groups. CONCLUSIONS Long-term hypoperfusion causes different degrees of morphologic alterations leading to degeneration. Preoperative analysis of regional contractility and perfusion-metabolism imaging does not distinguish the severity of morphologic alterations nor the functional outcome after revascularization. The insufficient act of self-preservation in hibernating myocardium may lead to a progressive structural degeneration with an incomplete and delayed recovery of function after restoration of blood flow.

The right ventricle: anatomy, physiology and clinical imaging

Not long ago the right ventricle (RV) was considered an “unnecessary” part of the normal circulation. While factually correct—ablation or replacement of the RV free wall can be well tolerated by experimental animals without reduction in cardiac output, and many surgical algorithms for congenital heart diseases culminate in a circulation devoid of a sub-pulmonary ventricle, a Fontan procedure, for example—it is clear that such circulations are far from normal. Furthermore, recent studies consistently demonstrate a central role for RV dysfunction in the prognosis and outcomes for a wide variety of acquired and congenital cardiac conditions. Consequently there has been a renewed interest in the singular role of the RV, as well as its influence on global function via biventricular interactions. In this review, we will discuss some of the challenges encountered in the measurement of RV volume and function in the context of the RV’s unique anatomic structure and physiology. The role of both ventricles is to propel blood forward in the circulation. To enable this mechanical role, ventricular function is intimately related to ventricular structure. However, the two ventricles differ. Morphologically, the RV is distinguished from the left ventricle (LV) by having coarser trabeculae, a moderator band, and a lack of fibrous continuity between its inlet and outflow valves. In the RV the pulmonary valve sits on a freestanding muscular infundibulum and the crista supraventricularis courses between it and the tricuspid valve to aid free wall contraction toward the interventricular septum. Because it normally operates at a lower pressure than the LV, the RV has a thinner wall. Its septal contour is indented by the dominant LV, producing a shape that is difficult to model geometrically (fig 1). Figure 1 Three dimensional reconstructions of the right ventricle (RV) illustrating its complex shape in a normal subject (A). RV remodelling in diseased hearts can result in profound shape change, as in this patient (B) with dilated RV due to severe pulmonary regurgitation following repair of tetralogy of Fallot. The mesh surface is the left ventricle. LV, left ventricle; P, pulmonary valve; RV, right ventricle; T, tricuspid valve. See Sheehan and Bolson14 for explanation of reconstruction method. Nearly all studies of ventricular fibre structure were performed on the LV.1 Dissection studies showed that its fibres course …