Mark J. Pirwitz

Genetic modification of the vessel wall. Comparison of surgical and catheter-based techniques for delivery of recombinant adenovirus.

BACKGROUND Gene transfer can potentially alter vessel wall biology and intervene in the pathogenesis of human disease. Although several methods for vector delivery have been described, systematic comparisons of these methods are unavailable. Therefore, this study compared three catheter-based strategies and a surgical technique to assess efficient and selective gene transfer to the vascular wall. METHODS AND RESULTS The common carotid arteries and internal jugular veins of New Zealand White rabbits were infected with recombinant adenovirus encoding either firefly luciferase or a nuclear-localizing variant of beta-galactosidase. Delivery of recombinant virus was achieved by one of four methods: (1) instillation within a surgically isolated vessel segment (dwell), (2) a double-balloon catheter, (3) a perforated balloon catheter (Wolinsky), or (4) an angioplasty balloon catheter coated with a hydrophilic adsorbent polymer (Hydrogel). Vessel segments were analyzed 4 days after infection for luciferase and beta-galactosidase activity and for the extent of injury to the vessel wall. Luciferase activity in vessels infected using the double-balloon method was substantially greater than that achieved by catheter-based methods (P < .05). The dwell and double-balloon methods yielded selective expression in intimal cells, whereas arteries infected using perforated or Hydrogel-coated balloon catheters demonstrated expression primarily in medial cells. Tissue injury was most pronounced with the perforated balloon catheter. CONCLUSIONS Prototype catheters permit relatively efficient direct gene transfer to vascular endothelium; however, delivery methods for targeting the medial cells are inefficient. Modifications are needed to optimize direct gene transfer and minimize tissue injury.

Adenoviral mediated gene transfer to atherosclerotic arteries after balloon angioplasty

The purpose of this study was to examine the pattern of catheter-mediated adenoviral gene transfer into atherosclerotic vessels subjected to balloon injury. Atherosclerotic lesions were created in the iliac arteries of New Zealand white rabbits fed with cholesterol. Balloon dilatation was performed at the angiographically defined region of maximal stenosis. Instillation of a recombinant adenoviral vector encoding beta Galactosidase was performed at the angioplasty site with either (1) a double-balloon catheter (n = 7 arterial segments), (2) a hydrogel-coated balloon (n = 3), (3) a perforated balloon (n = 3), or (4) a catheter with an inflatable circumferential helical ring (n = 4). Successful gene transfer reflected by expression of nuclear-localizing beta-galactosidase activity was observed in all sections displaying angioplasty effect. Genetically modified cells were located in pockets within the deep portions of the neointima, the media, and the adventitia immediately adjacent to dissection planes. Gene transfer to an atherosclerotic vessel subjected to balloon angioplasty is feasible with recombinant adenovirus vectors and currently available delivery catheters. The regions of the vessel wall that express the foreign protein are those which contribute most importantly to the proliferative cellular response which characterizes postangioplasty restenosis.

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.

Electrophysiologic effects of intranasal cocaine

Abstract In conclusion, intranasal cocaine, 2 mg/kg, induced no change in electrocardiographic intervals or a variety of electrophysiologic variables.

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.

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.

Effects of intravenous ethanol on diameter of epicardial coronary arteries

T here is controversy concerning the effects of ethanol on the coronary vasculature. In animals, ethanol causes inte;lse coronary arterial vasoconstriction.‘,2 In contrast, in man, intracoronary ethanol increases coronary blood flow without changing epicardial coronary arterial dimensions, presumably by dilating the small resistance vessels.3 Because of these conflicting results, we performed this study to assess the influence of intravenous ethanol on heart rate, systemic arterial pressure, and epicardial coronary arterial dimensions in humans. . . . We studied 16 patients (13 men and 3 women, aged 37 to 67 years) undergoing cardiac catheterization for the evaluation of chest pain. The protocol was approved by the Human Subjects Review Committee of the University of Texas Southwestern Medical Center, and all patients gave written, informed consent. No subject had a previous or ongoing problem with alcohol abuse. Antianginal medications were discontinued for >12 hours before the study; no patient smoked for >3 hours before study. All patients were studied in the fasting state after premeditation with oral diazepam 5 to 10 mg. An 8Fr sheath was inserted percutaneously in the femoral artery, through which a Judkins catheter was advanced to the ostium of the left coronary artery. Systemic arterial pressure was measured through the catheter, and heart rate was determined electrocardiographically. The heart rate-systolic arterial pressure product was used as an estimate of myocardial oxygen demand.4 An initial cineangiogram was performed to exclude narrowing of the left main coronary artery. Provided that

Use of the left ventricular peak systolic pressure/end-systolic volume ratio to predict symptomatic improvement with valve replacement in patients with aortic regurgitation and enlarged end-systolic volume

OBJECTIVES This study was designed to assess the left ventricular peak systolic pressure/end-systolic volume (PSP/ESV) ratio in predicting symptomatic improvement with valve replacement in patients with aortic regurgitation and enlarged left ventricular volume. BACKGROUND Patients with aortic regurgitation and a left ventricular end-systolic volume < or = 60 ml/m2 show symptomatic improvement with valve replacement, whereas the response of those with an enlarged end-systolic volume > 60 ml/m2 is mixed. Most benefit, but some do not. Valve replacement appears to help those whose end-systolic volume is enlarged because of excessive left ventricular afterload but appears to have little or no effect in those whose end-systolic volume is enlarged because of depressed left ventricular contractility. METHODS We studied 27 patients (21 men and 6 women aged 18 to 72 years) with moderate or severe aortic regurgitation, no other cardiovascular abnormalities and left ventricular end-systolic volume > 60 ml/m2. In this group we assessed the ability of preoperative variables routinely measured at cardiac catheterization to predict symptomatic improvement with valve replacement. RESULTS Of the 27 subjects, 1 (4%) died 51 days postoperatively. Six months postoperatively, symptoms had lessened in 17 patients (63%), were unchanged in 8 (29%) and had worsened in 1 (4%). By multivariate analysis, the PSP/ESV ratio was the strongest predictor of both functional class 6 months postoperatively (p = 0.026) and change in functional class from before operation to 6 months postoperatively (p = 0.033). By 6 months after valve replacement, all patients with a ratio > or = 1.72 mm Hg/ml per m2 were in functional class I or II; in contrast, of those with a ratio < 1.72 mm Hg/ml per m2, 31% were in functional class III, and 1 (8%) had died. CONCLUSIONS The PSP/ESV ratio may help to predict which patients with aortic regurgitation and enlarged left ventricular end-systolic volume will have symptomatic improvement with valve replacement.

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.

Intracardiac shunts resulting from transseptal catheterization for ablation of accessory pathways in otherwise normal hearts

In a series of 14 patients undergoing transseptal catheterization for ablation of left-sided accessory pathways, hydrogen appearance time was used to detect left-to-right shunting after removal of the catheter. Six of the 12 patients who had no evidence of shunt before catheterization had evidence of shunting after the procedure.