Poloxamer-188 as an adjunct to primary percutaneous transluminal coronary angioplasty for acute myocardial infarction.

Poloxamer-188 is a surfactant polymer with antithrombotic and hemorheologic properties that make it potentially useful as an adjunct to acute reperfusion strategies. Animal studies and early human studies have documented poloxamer-188 to be effective at improving myocardial salvage when used as an adjunct to intravenous thrombolytic therapy for acute myocardial infarction. The current trial was a prospective pilot study involving 150 patients who were randomized in a 2:1 fashion to a poloxamer-188 infusion for 48-hours versus placebo. The poloxamer-188 infusion was well tolerated subjectively. The only clinically significant laboratory abnormality noted was an elevation in the serum creatinine above 2.0 g/dl in 12% (n = 12) of the 98 poloxamer-188 treated patients versus 1 of the 52 (2%) of the placebo treated patients (p = 0.048). Clinical end points including reinfarction (1% vs 4%), cardiogenic shock (7% vs 6%), and death (9% vs 4%) were statistically similar in the poloxamer-188 and placebo groups, respectively (p = NS). Using quantitative nuclear techniques, final infarct size and myocardial salvage were statistically similar in the poloxamer-188 and placebo groups. Mean left ventricular ejection fractions 1 week post after infarction were 51% +/- 12% in the poloxamer-188 group and 52% +/- 13% in the placebo group (p = NS). Final infarct size, was not altered by the poloxamer- 188 infusion; however, it was significantly correlated with normal perfusion (Thrombolysis in Myocardial Infarction grade 3 flow) in the infarct vessel after angioplasty. This study documented poloxamer-188 to be ineffective as an adjunct to primary angioplasty for acute myocardial infarction and resulted in azotemia in 12% of the patients.

Comparison of front-loaded recombinant tissue-type plasminogen activator, anistreplase and combination thrombolytic therapy for acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 4 trial.

OBJECTIVES: The aim of our study was to determine a superior thrombolytic regimen from three: anistreplase (APSAC), front-loaded recombinant tissue-type plasminogen activator (rt-PA) or combination thrombolytic therapy. BACKGROUND: Although thrombolytic therapy has been shown to reduce mortality and morbidity after acute myocardial infarction, it has not been clear whether more aggressive thrombolytic-antithrombotic regimens could improve the outcome achieved with standard regimens. METHODS: To address this issue, 382 patients with acute myocardial infarction were randomized to receive in a double-blind fashion (along with intravenous heparin and aspirin) APSAC, front-loaded rt-PA or a combination of both agents. The primary end point "unsatisfactory outcome" was a composite clinical end point assessed through hospital discharge. RESULTS: Patency of the infarct-related artery (Thrombolysis in Myocardial Infarction [TIMI] grade 2 or 3 flow) at 60 min after the start of thrombolysis was significantly higher in rt-PA-treated patients (77.8% vs. 59.5% for APSAC-treated patients and 59.3% for combination-treated patients [rt-PA vs. APSAC, p = 0.02; rt-PA vs. combination, p = 0.03]). At 90 min, the incidence of both infarct-related artery patency and TIMI grade 3 flow was significantly higher in rt-PA-treated patients (60.2% had TIMI grade 3 flow vs. 42.9% and 44.8% of APSAC- and combination-treated patients, respectively [rt-PA vs. APSAC, p < 0.01; rt-PA vs. combination, p = 0.02]). The incidence of unsatisfactory outcome was 41.3% for rt-PA compared with 49% for APSAC and 53.6% for the combination (rt-PA vs. APSAC, p = 0.19; rt-PA vs. combination, p = 0.06). The mortality rate at 6 weeks was lowest in the rt-PA-treated patients (2.2% vs. 8.8% for APSAC and 7.2% for combination thrombolytic therapy [rt-PA vs. APSAC, p = 0.02; rt-PA vs. combination, p = 0.06]). CONCLUSIONS: Front-loaded rt-PA achieved significantly higher rates of early reperfusion and was associated with trends toward better overall clinical benefit and survival than those achieved with a standard thrombolytic agent or combination thrombolytic therapy. These findings support the concept that more rapid reperfusion of the infarct-related artery is associated with improved clinical outcome.

Cardiac catheterization and coronary angiography using 5 French preformed (Judkins) catheters from the percutaneous right brachial approach: a comparative analysis with the femoral approach.

This study describes a method for the performance of cardiac catheterization using 5 French preformed Judkins catheters from a percutaneous right brachial approach, and compares that technique to the more traditional percutaneous right femoral approach with 6 French catheters. One hundred consecutive patients requiring diagnostic left heart catheterization and selective coronary angiography were randomized according to femoral versus brachial arterial technique. Procedural efficiency, radiation exposure, and diagnostic film quality favored the femoral approach, while patient comfort, hemostasis time, time to ambulation, and decreased need for post-procedure nursing care favored the brachial approach. No differences were identified in complications. Cardiac catheterization from a right brachial artery percutaneous approach with 5 French preformed catheters has both advantages and disadvantages when compared with a more traditional femoral approach with 6 French catheters. Multiple factors should be considered before selecting an approach to diagnostic cardiac catheterization and each patient should be individually evaluated for determination of the optimal technique.

Myocardial infarct artery patency and reocclusion rates after treatment with duteplase at the dose used in the International Study of Infarct Survival-3. Burroughs Wellcome Study Group.

Duteplase, 98% double-chain recombinant tissue-type plasminogen activator, was administered intravenously in 488 patients with acute myocardial infarction in a multicenter, open, safety and patency study. Duteplase dosing was based on body weight. Duteplase was administered as a bolus of 0.04 MIU/kg of thrombolytic activity followed by 0.36 MIU/kg over 1 hour and 0.067 MIU/kg/hour for 3 additional hours. The patency rate of the infarct-related artery at 90 minutes was 69% (330 of 478). The reocclusion rate at 3 to 48 hours was 6% (18 of 301). Reinfarction occurred in 7.6% of patients (37 of 488), but 12 reinfarctions occurred after coronary angioplasty. Serious bleeding occurred in 7.6% of patients (37 of 488), predominantly at the catheterization entry site. There were 3 instances of central nervous system bleeding, 1 fatal. Fibrinogen levels declined to 83% of baseline at 24 hours. Weight-based dosing may explain the low incidence of serious bleeding in this study. The in-hospital mortality was 6.6% (32 of 488). This study documents that the dose of duteplase used in the International Study of Infarct Survival-3 results in a 90-minute coronary artery patency rate and safety profile comparable to those reported in published studies on the approved dose of alteplase.

Rest and exercise cardiovascular effects of terazosin in congestive heart failure.

This study investigated the acute effects of the alpha 1 antagonist terazosin on myocardial circulatory responses at rest and during exercise. Ten patients with congestive heart failure (class III and IV) underwent hemodynamic evaluation before and after a 5-mg oral dose of terazosin. At rest and during exercise, terazosin significantly decreased pulmonary capillary wedge pressure, systemic vascular resistance and mean arterial pressure while cardiac index increased. Stroke volume index increased (p less than 0.01) during exercise while left ventricular stroke work index remained unchanged in both experimental conditions. Terazosin administration significantly decreased both rest and exercise myocardial oxygen consumption while exercise coronary sinus oxygen content increased and arterial-coronary sinus oxygen difference diminished (p less than 0.05). Parallel with these changes, alpha blockade decreased the ratio of coronary blood flow to total cardiac output. Coronary vascular resistance remained unaltered with alpha blockade both at rest and during exercise. Coronary blood flow tended to diminish with decreased myocardial oxygen demand. Alpha 1 blockade induces systemic vasodilation and improves myocardial circulatory parameters without inducing coronary dilation or altering metabolic autoregulation.

Influence of exercise on coronary sinus blood flow determinations.

Consecutively measured values of coronary sinus blood flow were compared to assess the reproducibility of the coronary sinus thermodilution technique. Values measured at rest and during exercise were evaluated and the influence of the respiratory cycle on reproducibility was studied. Correlation of consecutive values revealed a coefficient of 0.94 at rest and 0.93 during exercise. Differences between mean values of consecutive measurements were nonsignificant. A comparison of the coefficients of variation at rest (8.50 +/- 7.09) and exercise (8.02 +/- 4.75) revealed no significant difference. Variation about mean coronary sinus blood flow due to inspiration and expiration was similar at rest and during exercise (42% and 37%, respectively). Provided that critical variables are closely monitored, the coronary sinus thermodilution technique is a highly reproducible technique in a clinically feasible setting.

Human and canine ventricular vasoactive intestinal polypeptide: decrease with heart failure.

Vasoactive intestinal polypeptide (VIP) is a systemic and coronary vasodilator that may have positive inotropic properties. Myocardial levels of VIP were assayed before and after the development of heart failure in two canine models. In the first, cobalt cardiomyopathy was induced in eight dogs; VIP (by radioimmunoassay) decreased from 35 +/- 11 pg/mg protein (mean +/- SD) to 5 +/- 4 pg/mg protein (P less than 0.05). In six dogs with doxorubicin-induced heart failure, VIP decreased from 31 +/- 7 to 11 +/- 4 pg/mg protein (P less than 0.05). In addition, VIP content of left ventricular muscle of resected failing hearts in 10 patients receiving a heart transplant was compared with the papillary muscles in 14 patients (five with rheumatic disease, nine with myxomatous degeneration) receiving mitral valve prostheses. The lowest myocardial VIP concentration was found in the hearts of patients with coronary disease (one patient receiving a transplant and three receiving mitral prostheses) (6.3 +/- 1.9 pg/mg protein). The other patients undergoing transplantation had an average ejection fraction of 17% +/- 6% and a VIP level of 8.8 +/- 3.9 pg/mg protein. The hearts without coronary artery disease (average ejection fraction of this group 62% +/- 10%) had a VIP concentration of 14.1 +/- 7.9 pg/mg protein, and this was greater than in hearts of the patients with coronary disease and the hearts of patients receiving a transplant (P less than 0.05). Myocardial catecholamines were also determined in 14 subjects; a weak correlation (r = 0.57, P less than 0.05) between the tissue concentrations of VIP and norepinephrine was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging of the human myocardium: a histologic study based upon endomyocardial biopsy.

This study assesses the effect of aging on human myocardial morphology. Fifteen patients, ranging in age from 28 to 75 with normal cardiac history, physical examination and noninvasive tests of left ventricular function, underwent right ventricular endomyocardial biopsy prior to cancer chemotherapy. Cell diameter, nuclear area and fibrosis were quantified by light microscopy. Semiquantitative methods of electron microscopy were used to grade lipofuscin deposition, tubular dilation, myofibrillar loss, folding of discs and lipid deposition. The results demonstrated that myocardial cell diameter correlated directly with age (r = 0.73, p less than 0.01) and systolic blood pressure (r = 0.51, p less than 0.05). Nuclear area (r = 0.76, p less than 0.01) and folded discs (r = 0.53, p less than 0.05), two signs of increased protein production also correlated with age. Lipid deposition (r = 0.40), tubular dilation (r = 0.31) and lipofuscin deposition (r = 0.20) increased with, but did not correlate significantly with age. Lipid deposition (r = 0.56, p less than 0.05) and tubular dilation (r = 0.43, p less than 0.05) did correlate with cell diameter. Thus, the aging myocardium is characterized by increased cell size and some degenerative changes.

Effect of vasoactive intestinal polypeptide on the canine cardiovascular system.

Our purpose was to determine the effect of vasoactive intestinal polypeptide (VIP) on the cardiovascular system with special emphasis on coronary vascular effects. In section I, VIP was infused into six healthy and six cobalt-cardiomyopathic dogs at two infusion rates (0.02 and 0.05 micrograms/kg/min). Left ventricular end diastolic pressure and mean systemic pressure fell significantly in both groups. Heart rate rose in both, and maximum systolic dP/dt increased in the myopathic group. Cardiac output and regional blood flows were determined by serial left atrial injections of radioactive 15 +/- 3 mum (mean +/- SD) microspheres. In both groups, blood flow increased significantly to the esophagus, pancreas, atria, and ventricles and to the endocardial and epicardial regions of the left ventricular free wall. Blood flow to the brain decreased. In section II, VIP was infused intravenously at 0.1 micrograms/kg/min into six anesthetized dogs with coronary sinus flow, pulmonary artery, and systemic artery catheters inserted. Cardiac index rose from baseline (3.1 +/- 0.5 to 4.8 +/- 1.3 L/min/m2, P less than 0.005), as did coronary blood flow (90 +/- 25 to 159 +/- 54 ml/min, P less than 0.005) during the VIP infusion. Myocardial oxygen consumption rose from 14.1 +/- 3.9 to 19.8 +/- 5.4 ml/min (P less than 0.001), but the aorta-to-coronary sinus O2 difference decreased from 157 +/- 19 ml/L to 132 +/- 42 ml/L (P less than 0.05), and the percent O2 extracted from coronary blood also decreased significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Postural influences on the hemodynamic responses to vasodilating drugs in congestive heart failure.

Supine and upright hemodynamic measurements were performed in 58 patients with congestive heart failure to assess the effects of postural change on the hemodynamic responses to vasodilating drugs. The patient population was divided into three treatment groups and was studied before and after isosorbide dinitrate, nifedipine, or clonidine treatment. When the hemodynamic responses in the upright position were compared with the supine values, isosorbide dinitrate (40 mg orally) evoked a greater reduction in mean systemic blood pressure and stroke volume with augmented increases in heart rate, mean pulmonary artery pressure, and pulmonary vascular resistance while the patient was upright. Nifedipine (10 mg orally) when studied in the upright position caused additional augmentation of cardiac output and stroke volume index with further reduction in total systemic vascular resistance compared with supine values. No position-related changes in hemodynamic measurements were noted with clonidine (0.1 mg orally).

Regional hemodynamic effects of clonidine in congestive heart failure.

Regional and central hemodynamic variables were ascertained in 10 patients with congestive heart failure before and after the oral administration of clonidine. Following the 0.2 mg dose, renal, hepatic, and limb blood flow remained unaltered, whereas a reduction was noted in heart rate (10%), mean systemic (14%), and pulmonary capillary wedge pressures (27%). Cardiac index and systemic vascular resistance fell slightly, however the changes were not statistically significant. Higher dose clonidine (0.4 mg) elicited similar regional hemodynamic effects whereas systemic vascular resistance significantly diminished (21%) and cardiac index remained unchanged. In congestive heart failure, the central antihypertensive agent, clonidine, effects a significant reduction in preload (left ventricular filling pressure) and afterload (systemic blood pressure) without markedly altering other central and regional hemodynamic variables.

Failure of percutaneous transluminal coronary angioplasty to stimulate platelet and prostaglandin activity.

Platelet function and prostaglandin activity were evaluated in nine patients with coronary artery disease undergoing percutaneous left anterior descending coronary artery angioplasty (PTCA) and compared to nine normal controls. Transcoronary measurements (arterial-coronary sinus) of platelet counts, mean platelet volume, platelet factor 4 (PF4), beta thromboglobulin, thromboxane (B2), and 6-keto-PGF 1 alpha were made. When compared to normal controls, the patients with coronary artery disease had higher circulating baseline levels of PF4 in the coronary sinus. There was no transcardiac production of any factor at baseline or immediately after infusion of nitroglycerin or performance of PTCA. These results suggest that PTCA does not grossly alter arachidonic acid metabolism or platelet activity.

Nifedipine in congestive heart failure: effects on resting and exercise hemodynamics and regional blood flow.

Ten patients with moderate to severe congestive heart failure (CHF) underwent central and regional hemodynamic measurements at rest and central hemodynamic measurements during exercise before and after the oral administration of nifedipine (0.2 mg/kg). Nifedipine significantly decreased systemic blood pressure, systemic vascular resistance, pulmonary artery pressure, pulmonary vascular resistance, and pulmonary capillary wedge pressure. Stroke volume and cardiac output increased after nifedipine. The measured parameters of left ventricular inotropy did not change significantly for this calcium channel blocker. While blood flow to renal, hepatic, and limb vascular beds increased (p less than 0.05 for renal and limb) after nifedipine, only limb blood flow increased in proportion to the increase in cardiac output, suggesting preferential dilatation of limb vasculature. Although initial-dose nifedipine did not increase exercise duration, it elicited an improvement in exercise hemodynamics by reducing systemic vascular resistance and pulmonary capillary wedge pressure and increasing stroke volume and cardiac output. The calcium channel blocker, nifedipine, can be administered safely in the setting of ventricular failure and appears to favorably alter resting and exercise hemodynamics. A select number of patients with CHF may benefit from its long-term administration.

Beneficial effects of nifedipine on rest and exercise myocardial energetics in patients with congestive heart failure.

Rest and exercise systemic hemodynamic parameters, coronary blood flow, and myocardial energetics were assessed before and 15 min after the sublingual administration of 20 mg of nifedipine in 10 patients with idiopathic congestive cardiomyopathy. When compared with control, nifedipine increased rest and exercise cardiac index by 37% and 28%, respectively (p less than .001). Peripheral vasodilation was demonstrated with a drop in systemic arterial pressure, exercise pulmonary capillary wedge pressure, and systemic vascular resistance (p less than .05). The calcium-channel blocker did not alter myocardial oxygen consumption; however, coronary blood flow increased by 32% at rest (p less than .01) while coronary vascular resistance diminished both at rest and after exercise compared with control (p less than .05). Nifedipine elicited a decrease in the rest and exercise aortocoronary sinus oxygen difference while the coronary sinus oxygen saturation increased (p less than .01). In this group of patients with idiopathic congestive cardiomyopathy, nifedipine enhanced myocardial performance while increasing coronary blood flow and favorably altering the myocardial oxygen supply-demand balance.

Hydralazine therapy in chronic congestive heart failure. Sustained central and regional hemodynamic responses.

Central and regional hemodynamic parameters were evaluated at baseline and following three months of placebo or hydralazine therapy (100 mg orally every eight hours) in 20 patients with idiopathic dilated cardiomyopathy. Both control (placebo) and hydralazine groups were comparable with respect to functional classification (New York Heart Association classes III and IV) and baseline hemodynamic variables. In the hydralazine group, cardiac index increased 25 percent (2.4 +/- 0.4 to 3.0 +/- 0.5 liters/minute/m2), renal blood flow increased 26 percent (648 +/- 199 to 815 +/- 229 ml/minute), and limb blood flow was augmented by 35 percent (6.8 +/- 3.0 to 9.2 +/- 4.6 ml/dl/minute) with long-term therapy. These changes were significant (all p less than 0.05) when compared with both baseline values and values in the control group. Both central and regional hemodynamic parameters remained unaltered in the control group. Long-term hydralazine therapy (three months) elicited a favorable circulatory response in this group of patients with chronic congestive heart failure. Central or regional hemodynamic tolerance to oral hydralazine failed to develop in the majority of patients.

Factors influencing the one-year mortality of dilated cardiomyopathy.

This study was designed to determine prognostic risk indicators of nonischemic dilated cardiomyopathy (DC). Sixty-nine patients were studied. Each patient underwent physical examination (including a history), electrocardiography, echocardiography, cardiac catheterization, 24-hour monitoring and endomyocardial biopsy. The mortality rate at 1 year was 35% (24 deaths). Univariate analysis revealed that the most powerful predictor of prognosis was the left intraventricular conduction delay (p = 0.003). The pulmonary capillary wedge pressure was also predictive of mortality (p = 0.005). Other significant factors, in order of importance, were ventricular arrhythmias (p = 0.007), mean right atrial pressure (p = 0.008), angiographic ejection fraction (p = 0.03), atrial fibrillation or flutter (p = 0.01) and the presence of an S3 gallop (p = 0.05). Factors such as duration of symptoms, presence of mitral regurgitation, end-diastolic diameter, myocardial cell size and percent fibrosis in the biopsy and treatment with vasodilators, antiarrhythmic and anticoagulant drugs were not significant predictors. Multivariate analysis was used to determine which combination of factors could most accurately predict survival and death. The most important factors were left conduction delay, ventricular arrhythmias and mean right atrial pressure. An equation was derived that can be applied to the prognosis of patients with DC. Thus, the clinical assessment of patients with DC can accurately predict the probability of surviving or dying in 1 year.

Reperfusion of the human myocardium by saphenous vein bypass grafts. Biochemical considerations.

The adenine nucleotide content of the human myocardium in the distribution of the left anterior descending coronary artery (LAD) was measured before and after saphenous vein bypass grafting. The purpose of the study were twofold: (1) to relate the level of adenosine triphosphate (ATP) before bypass grafting to the percent stenoses of the LAD and (2) to determine the benefit or lack of benefit of bypass grafting on ATP content. Eighteen patients with angiographically determined LAD lesions of 40% to 100% underwent bypass grafting with standard cardiopulmonary bypass and cardioplegia. Transmural needle biopsy specimens were obtained from the center of the area perfused by the LAD immediately before cross-clamping of the aorta and 30 minutes after reperfusion of the myocardium via the native LAD and the graft. The tissue was divided into thirds: The endocardial and epicardial thirds were analyzed for ATP by high-pressure liquid chromatography and the middle third was viewed by light microscopy. The percent narrowing of the LAD correlated well (r = -0.71) with the ratio of ATP to total adenine nucleotides (TAN) in the endocardium. Epicardial ATP did not correlate with the percent stenoses of the LAD. The endocardial ATP/TAN ratio increased in the group as a whole from 0.51 +/- 0.27 (mean +/- SD) to 0.64 +/- 0.26 (p less than 0.01) after bypass grafting, and this was most impressive in those eight patients with LAD lesions greater than 90% (0.32 +/- 0.20 before grafting to 0.60 +/- 0.29 after grafting, p less than 0.005). However, the epicardial ATP/TAN ratio decreased from 0.75 +/- 0.15 before grafting to 0.64 +/- 0.17 after grafting (p less than 0.05), and this decrease occurred regardless of the percent narrowing of the LAD. There was no difference in vacuolization between the pre-grafting and post-grafting biopsy specimens, and intramyocardial hemorrhage was not observed. This study has demonstrated a close relationship between the degree of LAD stenosis and endocardial ATP content. Also, the endocardium supplied by arteries with greater than 90% lesions had significantly increased ATP while the epicardium had decreased ATP content after bypass grafting.

Hemodynamic correlates for timing intervals, ejection rate and filling rate derived from the radionuclide angiographic volume curve.

This study was designed to more clearly define the relation between various invasive hemodynamic measurements and left ventricular (LV) timing intervals, ejection rate and filling rate derived from the radionuclide angiographic volume curve. Twenty-eight patients were studied with simultaneous intracardiac micromanometer pressure and dP/dt recordings, gated radionuclide angiography and M-mode echocardiography. These techniques permitted multiple variables of systolic and diastolic function to be measured at a constant atrial paced rate of 100 beats/min. There was a strong correlation between peak ejection rate and ejection fraction (r = -0.97) and between peak ejection rate and maximum positive dP/dt (r = -0.85). There also was a strong correlation between peak filling rate and maximum negative dP/dt (r = -0.85). A weaker correlation existed between the time constant of LV relaxation and the peak filling rate (r = -0.49) and between the LV end-diastolic pressure and the peak filling rate (r = -0.62). There was no correlation between the modulus of chamber stiffness and filling rates, and no association was observed between the time to peak filling rate and the hemodynamic variables. Thus, under the conditions studied, the measured peak ejection and filling rate, determined from the radionuclide angiographic volume curve, correlated well with accepted invasive hemodynamic measurements.