Bioresorbable microporous stents deliver recombinant adenovirus gene transfer vectors to the arterial wall.

The use of intravascular stents as an adjunct for percutaneous transluminal revascularization is limited by two principal factors, acute thrombosis and neointimal proliferation, resulting in restenosis. To overcome these limitations, we have investigated the potential of microporous bioresorbable polymer stents formed from poly(L-lactic acid) (PLLA)/poly(epsilon-caprolactone) (PCL) blends to function both to provide mechanical support and as reservoirs for local delivery of therapeutic molecules and particles to the vessel wall. Tubular PLLA/PCL stents were fabricated by the flotation-precipitation method, and helical stents were produced by a casting/winding technique. Hybrid structures in which a tubular sheath is deposited on a helical skeleton were also generated. Using a two-stage solvent swelling technique, polyethylene oxide has been incorporated into these stents to improve hydrophilicity and water uptake, and to facilitate the ability of these devices to function as drug carriers. Stents modified in this manner retain axial and radial mechanical strength sufficient to stabilize the vessel wall against elastic recoil caused by vasoconstrictive and mechanical forces. Because of the potential of direct gene transfer into the vessel wall to ameliorate thrombosis and neointimal proliferation, we have investigated the capacity of these polymer stents to function in the delivery of recombinant adenovirus vectors to the vessel wall. In vitro, virus stock was observed to readily absorb into, and elute from these devices in an infectious form, with suitable kinetics. Successful gene transfer and expression has been demonstrated following implantation of polymer stents impregnated with a recombinant adenovirus carrying a nuclear-localizing betaGal reporter gene into rabbit carotid arteries. These studies suggest that surface-modified polymer stents may ultimately be useful adjunctive devices for both mechanical support and gene transfer during percutaneous transluminal revascularization.

A critical reappraisal of the oximetric assessment of intracardiac left-to-right shunting in adults.

Although the oximetric analysis of blood from the right heart chambers is the most commonly used method for assessing the presence of intracardiac left-to-right shunting, the data the analysis is based on are limited. In addition, uncertainty exists concerning the best way of estimating the mixed venous oxygen content in subjects with intraatrial left-to-right shunting. In 102 adults without left-to-right shunting, blood was obtained from the venae cavae and right heart chambers to measure oxygen content. The limits of normality of oxygen content differences were 0.5 ml/dl from venae cavae to right atrium, 0.6 ml/dl from right atrium to right ventricle, and 0.9 ml/dl from right ventricle to pulmonary artery. The pulmonary arterial oxygen content was best estimated by combining the superior and inferior vena caval oxygen contents according to the formula (2[SVC] + 3[IVC]) divided by 5, where SVC is the superior vena cava and IVC is the inferior venae cava. These data provide new oximetric criteria for establishing the presence of intracardiac left-to-right shunting in adults.

Comparison of quantitation of left ventricular volume, ejection fraction, and cardiac output in patients with atrial fibrillation by cine magnetic resonance imaging versus invasive measurements.

Currently available invasive and noninvasive techniques for the determination of left ventricular end-diastolic and end-systolic volumes, ejection fraction, and cardiac output are more time-consuming and potentially less accurate in patients with atrial fibrillation (AF) than in those with sinus rhythm. Although magnetic resonance imaging (MRI) can rapidly and accurately measure these variables in patients with sinus rhythm, its ability to do so in subjects with AF is not known. To determine if left ventricular volumes, ejection fraction, and cardiac output can be measured accurately in patients with AF using MRI, 26 subjects (13 women and 13 men, aged 15 to 76 years) in sinus rhythm (n = 13) or AF (n = 13) underwent MRI followed immediately by invasive measurements of these indexes. For those in AF, MRI measurements of left ventricular end-diastolic volume, end-systolic volume, stroke volume, ejection fraction, and cardiac output correlated well with catheterization measurements (r = 0.90, 0.90, 0.95, 0.85, and 0.90, respectively). In addition, the mean difference between MRI and catheterization measurements was similar in subjects with AF and in those with sinus rhythm. Compared with standard invasive measurements, MRI provides an accurate noninvasive determination of left ventricular volumes, ejection fraction, and cardiac output in patients with AF.

Intranasal nicotine spray does not augment the adverse effects of cigarette smoking on myocardial oxygen demand or coronary arterial dimensions.

PURPOSE: Nicotine replacement therapy has become a popular therapy for smokers attempting to stop smoking. Unfortunately, some subjects continue to smoke while receiving it. Since nicotine is believed to be the primary constituent of cigarette smoke responsible for its acute adverse effects on myocardial oxygen supply and demand, concomitant nicotine replacement therapy and smoking theoretically could provoke a marked decrease in myocardial oxygen supply and increase in demand. This study was performed to assess the effects of cigarette smoking with and without concomitant intranasal nicotine spray on: (a) myocardial oxygen demand, (b) coronary arterial dimensions, and (c) the development of acute cardiovascular tolerance. PATIENTS AND METHODS: In 19 smokers referred for cardiac catheterization for the evaluation of chest pain, we assessed the effects of cigarette smoking with and without concomitant intranasal nicotine spray on: (a) heart rate-systolic arterial pressure product (an estimate of myocardial oxygen demand), (b) coronary arterial dimensions (measured with computer-assisted quantitative arteriography), and (c) the development of acute cardiovascular tolerance. RESULTS: Smoking a first cigarette increased rate pressure product (P < 0.001) and decreased coronary arterial dimensions (P < 0.0001). Subsequently, neither variable was altered by intranasal nicotine spray or a second cigarette. Despite a substantial increase in serum nicotine concentration with nicotine spray and smoking, acute cardiovascular tolerance appears to develop. CONCLUSIONS: Cigarette smoking causes an increase in myocardial oxygen demand and concomitant coronary arterial vasoconstriction. However, further increases in the serum nicotine concentration do not cause a greater increase in demand or decrease in coronary arterial dimensions. These data suggest that humans acutely develop tolerance to an increasing nicotine concentration, thereby helping to explain the apparent lack of a potential synergistic adverse effect associated with continued smoking during nicotine replacement therapy.

Improved bioresorbable microporous intravascular stents for gene therapy.

Drug imbibing microporous stents are under development at a number of centers to enhance healing of the arterial wall after balloon coronary angioplasty procedures. The authors improved the mechanical strength and reservoir properties of a biodegradable microporous stent reported to this Society in 1994. A combined tubular/helical coil stent is readily fabricated by flotation/precipitation and casting/ winding techniques. A two stage solvent swelling technique allows precise adjustment of the surface hydrophilic/hydrophobic balance. These developments permit seven-fold improvement in drug capacity without significantly altering mechanical properties. Stents modified in this manner retain tensile and compressive strength and are suitable for remote deployment. Elution kinetics of these modified stents suggest they are suitable for gene delivery. Successful gene transfer and transmural expression have been demonstrated after implantation of stents impregnated with a recombinant adenovirus carrying a nuclear localizing beta-galactosidase reporter gene into rabbit carotid arteries. These studies suggest that surface modified, bioresorbable polymer stents ultimately may be useful adjunctive devices for gene transfer during percutaneous transluminal revascularization.

Incidence and treatment of elastic recoil occurring in the 15 minutes following successful percutaneous transluminal coronary angioplasty.

This study was performed (1) to assess the incidence and magnitude of elastic recoil occurring within 15 minutes of successful coronary angioplasty, and (2) to determine the effect of subsequent additional balloon inflations on coronary luminal diameter in patients displaying substantial recoil. The coronary angiograms of 50 consecutive patients who underwent a successful percutaneous transluminal coronary angioplasty were analyzed using computer-assisted quantitative analysis. The patients were divided into 2 groups based on the magnitude of early elastic recoil following angioplasty: those with < or = 10% (group I, n = 30) and those with > 10% (group II, n = 20) loss of minimal luminal diameter as assessed by comparing the angiogram obtained immediately after successful angioplasty with that obtained 15 minutes later. The 2 groups were similar in clinical, angiographic, and procedural characteristics. Of the 20 group II subjects, 18 (90%) underwent repeat balloon dilatations, and 2 patients (10%) had no further intervention. After additional balloon inflations were performed in these 18 patients, 16 (90%) had a final result with < 10% loss of minimal luminal diameter 15 minutes later. In conclusion, elastic recoil 15 minutes after apparently successful percutaneous transluminal coronary angioplasty is frequent, occurring in approximately 40% of patients, and is attenuated in 90% of subjects with additional balloon inflations. The resultant larger lumen diameter may exert a salutary effect on long-term outcome.

Effects of the intracoronary infusion of cocaine on coronary arterial dimensions and blood flow in humans.

This study was done to assess the influence of large concentrations of cocaine (infused into the left coronary artery) on coronary arterial dimensions and blood flow in humans. In 20 subjects undergoing cardiac catheterization, incrementally increasing doses of (1) saline solution (n = 10, controls) or (2) cocaine hydrochloride (n = 10) were infused into the left coronary artery, and the effects on heart rate, systemic arterial pressure, coronary sinus blood flow, and coronary arterial dimensions were measured. Saline solution induced no change in any variable. With the infusion of cocaine, there was an incremental increase in its concentration in the systemic (femoral arterial) and coronary (coronary sinus) circulations (maximal concentrations, 0.14 +/- 0.06 [mean+/-SD] and 3.50 +/- 0.70 mg/L, respectively). At the maximal cocaine infusion rate, heart rate and diastolic arterial pressure increased slightly, but coronary sinus blood flow and the dimensions of nondiseased and diseased coronary arterial segments did not change. Thus, intracoronary infusion of cocaine in an amount sufficient to achieve a high concentration in the coronary circulation does not induce epicardial coronary arterial vasoconstriction or alter blood flow.

Utility of the 12-lead electrocardiogram in identifying underlying coronary artery disease in patients with depressed left ventricular systolic function.

We assessed the utility of the 12-lead electrocardiogram (ECG) in identifying severe coronary artery disease (CAD) in patients with depressed left ventricular (LV) systolic function. In 336 patients referred for cardiac catheterization with LV ejection fractions < 0.50, we compared the 12-lead ECG of those with and without CAD by multivariate analysis. The sensitivities, specificities, and positive and negative predictive values of all dichotomous electrocardiographic variables for identifying the presence of severe CAD were determined. In comparison to subjects with CAD, those without disease were more likely to exhibit left-axis deviation (p = 0.01), left bundle branch block (p < 0.001), or LV hypertrophy (p < 0.001), and less likely to exhibit pathologic inferior Q waves (p < 0.001). The presence of anterior or any Q waves was similar between the groups. The presence of any diagnostic Q wave had a positive predictive value of 92%, sensitivity of 57%, and specificity of 80% for identifying severe CAD. In patients with LV systolic dysfunction, the 12-lead ECG is insensitive and nonspecific for identifying those with concomitant severe CAD.

Assessment of coronary arterial flow and flow reserve in humans with magnetic resonance imaging.

BACKGROUND: The noninvasive measurement of absolute epicardial coronary arterial flow and flow reserve would be useful in the evaluation of patients with coronary circulatory disorders. Phase-contrast magnetic resonance imaging (PC-MRI) has been used to measure coronary arterial flow in animals, but its accuracy in humans is unknown. METHODS AND RESULTS: Twelve subjects (7 men, 5 women: age 44 to 67 years) underwent PC-MRI measurements of flow in the left anterior descending coronary artery or one of its diagonal branches at rest and after administration of adenosine (140 microgram . kg(-1) . min (-1) IV). Immediately thereafter, intracoronary Doppler velocity (IDV) and flow measurements were made during cardiac catheterization at rest and after intravenous administration of adenosine. For the 12 patients, the correlation between MRI and invasive measurements of coronary arterial flow and coronary arterial flow reserve was excellent: coronary flow (MRI) (mL/min)= 0.85 x coronary flow (IDV) (mL/min)+17 (mL/min), r=.89, and coronary flow reserve (MRI) =0.79 x coronary velocity reserve (IDV) + 0.34, r=.89. For the range of coronary arterial flows (18 to 161 mL/min) measured by MRI, the limit of agreement between MRI and catheterization measurements of flow was -13+/-30 mL/min; for the range of coronary reserves (0.7 to 3.7) measured by MRI, the limit of agreement between the two techniques was 0.1+/-0.4. CONCLUSIONS: Cine velocity-encoded PC-MRI can noninvasively measure absolute coronary arterial flow in the left anterior descending artery in humans. PC-MRI can detect pharmacologically induced changes in coronary arterial flow and can reliably distinguish between those subjects with normal and abnormal coronary artery flow reserve.

Influence of metoprolol on heart rate variability in survivors of remote myocardial infarction.

We assessed the influence of metoprolol on heart rate variability in survivors of remote myocardial infarction. In 43 survivors of myocardial infarction 12 to 18 months previously (26 men and 17 women, aged 38 to 69 years), two 24-hour ambulatory electrocardiograms were recorded 2 weeks apart. In patients in group A (n=28), who had taken metoprolol for the previous year, the drug was discontinued for 2 weeks, after which the first recording was done. The second recording was done 2 weeks after metoprolol was resumed. In patients in group B (n=15), who had not taken metoprolol for the previous year, it continued to be withheld, and two 24-hour recordings were done 2 weeks apart. In group A, metoprolol increased the time domain variables indicative of enhanced vagal tone; root-mean-square successive difference in normal RR (NN) intervals was 20 +/- 11 ms (mean +/- SD) without and 24 +/- 9 ms with metoprolol (p<0.05), and the proportion of NN that differ by >50 ms (pNN50%) was 3.6 +/- 6.0 without and 5.5 +/- 6.0 with metoprolol (p<0.05). In the frequency domain, the logarithms of the 24-hour very low frequency and the 24-hour high-frequency power (reflecting parasympathetic activity) were increased (5.12 +/- 1.03 and 4.48 +/- 1.51, respectively, without metoprolol; 5.32 +/- 0.99 and 4.83 +/- 1.24, respectively, with metoprolol, p <0.05 for both). Thus, in survivors of remote myocardial infarction, metoprolol enhances parasympathetic cardiac activity in the time and frequency domain measures of heart rate variability.

Magnetic resonance imaging assessment of the severity of mitral regurgitation. Comparison with invasive techniques.

BACKGROUND: In the patient with mitral regurgitation who is being considered for valvular surgery, cardiac catheterization is usually performed to quantify the severity of regurgitation and to determine its influence on left ventricular volumes and systolic function. Magnetic resonance imaging (MRI) potentially provides a rapid, noninvasive method of acquiring these data. Thus, this study was done to determine whether MRI can reliably measure the magnitude of mitral regurgitation and evaluate the effect of regurgitation on left ventricular volumes and systolic function. METHODS AND RESULTS: Twenty-three subjects (14 women and 9 men 15 to 72 years of age) with (n = 17) or without (n = 6) mitral regurgitation underwent MRI scanning followed immediately by cardiac catheterization. The presence (or absence) of valvular regurgitation was determined, and left ventricular volumes and regurgitant fraction were quantified during each procedure. There was excellent correlation between invasive and MRI assessments of left ventricular end-diastolic (r = .95) and end-systolic (r = .95) volumes and regurgitant fraction (r = .96). All MRI examinations were completed in < 28 minutes. CONCLUSIONS: In the patient with mitral regurgitation, MRI compares favorably with cardiac catheterization for assessment of the magnitude of regurgitation and its influence on left ventricular volumes and systolic function.

No association between plasma lipoprotein(a) concentrations and the presence or absence of coronary atherosclerosis in African-Americans.

Elevated plasma concentrations of lipoprotein(a) [Lp(a)] are associated with coronary atherosclerosis in Caucasians. Although African-Americans have a higher median plasma Lp(a) concentration than Caucasians, they do not have a greater incidence of coronary atherosclerosis. This study was performed to determine whether the plasma concentration of Lp(a) is associated with coronary atherosclerosis in African-Americans. The fasting plasma concentrations of Lp(a) and lipoproteins were measured in 140 African-American subjects (62 men, 78 women, aged 31 to 80 years) 18 +/- 16 months (mean +/- SD) after they underwent coronary angiography: 72 had angiographically normal coronary arteries and 68 had > 70% luminal diameter narrowing of one or more major epicardial coronary arteries. The groups were similar in age, sex, and other risk factors for atherosclerosis. The subjects with coronary artery disease had higher plasma concentrations of total cholesterol, triglycerides, and VLDL and LDL cholesterol (P = .04) and lower concentrations of HDL cholesterol (P = .0001) than subjects without coronary artery disease, but there was no significant difference in the plasma concentration of Lp(a). The distribution of apolipoprotein(a) alleles by size was also not significantly different between the two groups. These results suggest that the plasma concentration of Lp(a) is not an independent risk factor for coronary artery disease in African-Americans.

Assessment of left-to-right intracardiac shunting by velocity-encoded, phase-difference magnetic resonance imaging. A comparison with oximetric and indicator dilution techniques.

BACKGROUND: Velocity-encoded, phase-difference magnetic resonance imaging (MRI) has been shown to provide an accurate assessment of shunt magnitude in patients with large atrial septal defects, but its ability to determine shunt magnitude in patients with intracardiac left-to-right shunts of various locations and sizes has not been evaluated in a prospective and blinded manner. The objective of the present study was to determine whether velocity-encoded, phase-difference MRI can assess the magnitude of intracardiac left-to-right shunting in humans. METHODS AND RESULTS: Twenty-one subjects (15 women and 6 men; age range, 15 to 72 years) underwent velocity-encoded, phase-difference MRI measurements of flow in the proximal aorta and pulmonary artery, followed immediately by cardiac catheterization. The presence of left-to-right intracardiac shunting was assessed with hydrogen inhalation, after which shunt magnitude was measured by the oximetric and indocyanine green techniques. Of the 21 patients, 12 had left-to-right intracardiac shunting detected by hydrogen inhalation. There was a good correlation (r = .94) between the invasive and MRI assessments of shunt magnitude. In comparison to oximetry and indocyanine green, MRI correctly identified the 12 patients with a ratio of pulmonary to systemic flow (Qp/Qs) of < 1.5 (9 without intracardiac shunting and 3 with small shunts) and the 9 patients with a Qp/Qs of > or = 1.5 (6 with atrial septal defect, 1 with ventricular septal defect, 1 with patent ductus arteriosus, and 1 with both atrial septal defect and patent ductus arteriosus). CONCLUSIONS: Compared with measurements obtained during cardiac catheterization, velocity-encoded, phase-difference MRI measurements of flow in the proximal great vessels can reliably assess the magnitude of intracardiac left-to-right shunting.

Quantitation of cardiac output with velocity-encoded, phase-difference magnetic resonance imaging.

Velocity-encoded, phase-difference magnetic resonance imaging (MRI) previously has been used to measure flow in the aorta, as well as in the pulmonary, carotid, and renal arteries, but these measurements have not been validated against currently accepted invasive techniques. To determine the accuracy of velocity-encoded, phase-difference MRI measurements of cardiac output, 23 subjects (11 men and 12 women, aged 15 to 72 years) underwent velocity-encoded, phase-difference MRI measurements of cardiac output in the proximal aorta, followed immediately by cardiac catheterization, with measurement of cardiac output by the Fick principle and by thermodilution. For MRI, Fick, and thermodilution measurements, stroke volume was calculated by dividing cardiac output by heart rate. The magnetic resonance images were acquired in 1 to 3 minutes. For all patients, the agreement between measurements of stroke volume was 3 +/- 9 ml for MRI and Fick, -3 +/- 11 ml for MRI and thermodilution, and 0 +/- 8 ml for MRI and the average of Fick and thermodilution. Compared with standard invasive measurements, velocity-encoded, phase-difference MRI can accurately and rapidly determine cardiac output.

Influence of cocaine, ethanol, or their combination on epicardial coronary arterial dimensions in humans.

BACKGROUND: Cocaine and ethanol are often abused concomitantly, and this combination may be more lethal than either substance alone. Although previous studies showed that cocaine causes coronary arterial vasoconstriction, the combined effect of cocaine and ethanol on the coronary vasculature in humans is unknown. Thus, we assessed the effects of intranasal cocaine, intravenous ethanol, or a cocaine-ethanol combination on heart rate, systemic arterial pressure, and coronary arterial dimensions in humans. METHODS: Thirty-four subjects with chest pain (27 men and seven women, aged 34 to 67 years) who were referred for catheterization received one of the following pharmacologic interventions: (1) intranasal (2 mL) and intravenous (5 mL/kg) saline (n = 8 [group A]); (2) intranasal cocaine (2 mg/kg) and intravenous saline (5 mL/kg) (n = 9 [group B]); (3) intranasal saline (2 mL) and intravenous 10% ethanol (5 mL/kg) (n = 9 [group C]); or (4) intranasal cocaine (2 mg/kg) and intravenous 10% ethanol (5 mL/kg) (n = 8 [group D]). Heart rate, systemic arterial pressure, left coronary arterial dimensions (by computer-assisted quantitative angiography), as well as blood cocaine, ethanol, and cocaine metabolite concentrations were measured before and 30, 60, and 90 minutes after initiation of the intravenous infusions. RESULTS: No hemodynamic or angiographic changes were observed in the group A (saline) subjects. In the group B (cocaine) subjects, the heart rate-systolic arterial pressure product increased by 5% and 10% at 30 and 90 minutes, respectively, and coronary arterial diameter decreased by 14% at these times. In the group C (ethanol) subjects, no hemodynamic changes were noted, but coronary arterial diameters increased by 12%, 11%, and 12% at 30, 60, and 90 minutes, respectively. In the group D (cocaine-ethanol) patients, rate-pressure product increased by 17%, 10%, and 16%, and coronary arterial diameters increased by 7%, 12%, and 13%, at 30, 60, and 90 minutes, respectively. CONCLUSION: The combination of intranasal cocaine and intravenous ethanol causes an increase in the determinants of myocardial oxygen demand. However, it also causes a concomitant increase in epicardial coronary arterial diameter.

Noninvasive determination of infarct artery patency by cine magnetic resonance angiography.

BACKGROUND: In survivors of myocardial infarction, restoration of antegrade flow in the infarct artery reduces morbidity and mortality. At present, coronary artery patency must be assessed invasively with contrast angiography. A noninvasive method of evaluating infarct artery patency would be useful in managing survivors of infarction. This study was performed to determine whether magnetic resonance (MR) imaging could reliably assess infarct artery patency in this patient population. METHODS AND RESULTS: Eighteen survivors of myocardial infarction (11 men and 7 women, aged 35 to 74 years) who were consecutively referred for cardiac catheterization underwent contrast coronary angiography and cine MR coronary angiography. Sequential overlapping images of the infarct artery were acquired with cine MR during 15- to 20-second periods of breath-holding. In each study, proximal, middle, and distal segments of infarct arteries were classified as having antegrade, collateral, or no flow. The infarct artery was the left anterior descending in 10 patients, the right anterior descending in 7, and the circumflex in 1. When compared with the results of contrast angiography, MR imaging correctly identified the presence or absence of antegrade flow in the infarct artery of all 18 patients. In addition, cine MR coronary angiography with presaturating pulses correctly established the presence or absence of collateral filling of the distal portion of occluded arteries in 6 of 7 subjects. CONCLUSIONS: In survivors of myocardial infarction, cine MR coronary angiography can reliably determine the patency and direction of flow in the infarct artery.