Douglas K. Stewart

Noninvasive Doppler determination of cardiac output in man. Clinical validation.

A noninvasive technique for assessing cardiac output (CO) was evaluated by comparing it with thermodilution determinations in patients in the intensive care unit. The new method uses pulsed ultrasound to measure aortic diameter and continuous-wave Doppler ultrasound to obtain aortic blood velocity. An initial study evaluating just the velocity measurement showed that changes of the Doppler index of output (DI) correlated well with those of thermodilution cardiac output (TDCO). Linear regresson analysis yielded ADI = 0.87 ATDCO + 0.14 (r = 0.83, n = 95). Using a university research instrument these measurements were possible in 54 of 60 patients (90%). A second study using a prototype commercial device incorporated the diameter measurement. Ultrasonic cardiac output (UCO), calculated as the time integral of velocity multiplied by the aortic area, was compared to TDCO. The data, obtained from 45 of 53 patients (85%), are described by the linear regression UCO = 0.95TDCO + 0.38 (r = 0.94, n = 110) over a range of 2–11 I/min. Patients with aortic stenosis, aortic insufficiency or a prosthetic valve have been excluded from the second study due to conditions likely to violate the assumptions upon which the calculation of absolute cardiac output is based. These results indicate that accurate CO can be measured by noninvasive ultrasound in most patients. The technique may be useful for extended CO monitoring in acute care patients and for CO assessment in many other types of patients undergoing diagnostic studies and the rapeutic interventions.

Proliferation in primary and restenotic coronary atherectomy tissue. Implications for antiproliferative therapy.

On the basis of animal models of arterial injury, smooth muscle cell proliferation has been posited as a dominant event in restenosis. Unfortunately, little is known about this proliferation in the human restenotic lesion. The purpose of this study was to determine the extent and time course of proliferation in primary and restenotic coronary atherectomy-derived tissue. Primary (n = 118) and restenotic (n = 100) coronary atherectomy specimens were obtained from 211 nonconsecutive patients. Immunocytochemistry for the proliferating cell nuclear antigen (PCNA) was used to gauge proliferation in the atherectomy specimens. The identity of PCNA-positive cells was then determined using immunohistochemical cell-specific markers. Eighty-two percent of primary specimens and 74% of restenotic specimens had no evidence of PCNA labeling. The majority of the remaining specimens had only a modest number of PCNA-positive cells per slide (typically < 50 cells per slide). In the restenotic specimens, PCNA labeling was detected over a wide time interval after the initial procedure (eg, 1 to 390 days), with no obvious proliferative peak. Cell-specific immunohistochemical markers identified primary and restenotic PCNA-positive cells as smooth muscle cells, macrophages, and endothelial cells. In conclusion, the findings were as follows: (1) Proliferation in primary and restenotic coronary atherectomy specimens, as indicated by PCNA labeling, occurs infrequently and at low levels. (2) The response to injury in existing animal models of angioplasty may follow a very different course of events from the clinical reality in human atherosclerotic coronary arteries and may help explain why current approaches to restenosis therapy have been ineffective.

Osteopontin is synthesized by macrophage, smooth muscle, and endothelial cells in primary and restenotic human coronary atherosclerotic plaques.

How an atherosclerotic plaque evolves from minimal diffuse intimal hyperplasia to a critical lesion is not well understood. Cellular proliferation is a relatively infrequent and modest event in both primary and restenotic coronary atherectomy specimens, leading us to believe that other processes, such as the formation of extracellular matrix, cell migration, neovascularization, and calcification might be more important for lesion formation. The investigation of proteins that are overexpressed in plaque compared with the normal vessel wall may provide clues that will help determine which of these processes are key to lesion pathogenesis. One such molecule, osteopontin (OPN), is an arginine-glycine-aspartate-containing acidic phosphoprotein recently shown to be a novel component of human atherosclerotic plaques and selectively expressed in the rat neointima following balloon angioplasty. Using in situ hybridization and immunohistochemical methods, we demonstrate that in addition to macrophages, smooth muscle and endothelial cells synthesize OPN mRNA and protein in human coronary atherosclerotic plaque specimens obtained by directional atherectomy. In contrast, OPN mRNA and protein were not detected in nondiseased vessel walls. Furthermore, extracellular OPN protein collocalized with sites of early calcification in the plaque that were identified with a sensitive modification of the von Kossa staining technique. These findings, combined with studies showing that OPN has adhesive, chemotactic, and calcium-binding properties, suggest that OPN may contribute to cellular accumulations and dystrophic calcification in atherosclerotic plaques.

Chlamydia pneumoniae strain TWAR antibody and angiographically demonstrated coronary artery disease.

A recent case-control study from Finland reported a strong association between high antibody titers to Chlamydia pneumoniae, strain TWAR, and both chronic coronary heart disease and acute myocardial infarction. The current case-control study investigated the relation between C. pneumoniae immunoglobulin G antibody titers and angiographically diagnosed coronary artery disease. Cases (n = 461) were angiography patients with at least one coronary artery lesion occupying at least 50% of the luminal diameter. Controls (n = 95) were angiography patients with no demonstrable coronary artery disease. After standardization for age and gender, the geometric mean antibody titer was higher for cases than for controls (30.0 versus 24.0, p = 0.04). The estimated risk of coronary artery disease, adjusted for age and gender, was greater among subjects with high (greater than or equal to 1:64) antibody titers than among subjects with low (less than or equal to 1:8) antibody titers (relative risk, 2.0; 95% confidence interval, 1.0-4.0). The risk associated with a high antibody titer was particularly great for coronary artery disease with five or more lesions (relative risk, 2.8; 95% confidence interval, 1.2-7.0). The results of this cross-sectional study support an association between infection with C. pneumoniae and coronary artery disease.

Left ventricular function before and following aortic valve replacement.

Twenty-four patients with aortic valve disease were studied before and 19 ± 12 months following valve replacement with a well functioning prosthesis. Biplane left ventricular angiography and pressures were utilized to determine end-diastolic volume/M2 (EDV), end-systolic volume/m2 (ESV), ejection fraction (EF), left ventricular mass/M2 (LVM) and stroke work (SW). There were nine patients with aortic stenosis (AS), ten patients with combined stenosis and regurgitation (AS-AR), and five patients with aortic regurgitation (AR). Following surgery, patients with regurgitation preoperatively showed marked regression in EDV and ESV. All groups demonstrated regression in LVM. Fifteen patients with a normal EF preoperatively (65 ± 11%percnt;) had no change after surgery; the nine patients with a low EF before surgery (38 ± 8%percnt;) had a normal EF after surgery (60 ± 16%percnt;). We conclude that left ventricular dilatation, hypertrophy, and reduced left ventricular pump function are largely reversible after successful aortic valve replacement.

Variability in the measurement of regional left ventricular wall motion from contrast angiograms.

Four types of variability affecting quantification of regional wall motion from contrast left ventriculograms (LVgrams) were studied. These included beat-to-beat variability in 24 LVgrams, intraobserver and interobserver variability in 20 LVgrams, and study-to-study variability in serial LVgrams of 21 patients with stable coronary artery disease. Motion was measured at 100 equidistant chords perpendicular to a center line drawn midway between the end-diastolic and end-systolic contours and normalized for heart size. Variability was computed as the absolute difference between observations. Beat-to-beat, intraobserver, and interobserver variability at the 100 chords were similar, averaging 14%, 14%, and 17%, respectively, of the mean motion in 64 patients with normal ventriculograms. Study-to-study variability was significantly higher, averaging 30% of mean normal motion, but was reduced when regional motion was calculated as the mean motion of chords within a region of interest. Variability peaked at the apex. Realignment to correct for cardiac rotation significantly increased variability. Investigators whose methods of wall motion analysis rely on identification of the apex as a landmark should be aware of this source of potential variability and error.

Diltiazem-induced blockade of sympathetically mediated constriction of normal and diseased coronary arteries: lack of epicardial coronary dilatory effect in humans.

To determine mechanisms of benefit from diltiazem, 13 patients with coronary disease performed sustained isometric handgrip exercise and repeated the procedure during intravenous infusion of diltiazem (0.25 mg/kg bolus followed by 0.003 mg/kg/min). Cardiovascular responses to handgrip, diltiazem, their combination, and nitroglycerin were assessed by hemodynamic and electrocardiographic measurements and by computer-assisted measurements of normal and diseased segments of epicardial coronary arteries. Handgrip produced increases in heart rate (12%; p less than .001), pulmonary arterial pressure (19%; p less than .005), and pulmonary wedge pressure (33%; p less than .005). Diltiazem produced significant reductions in heart rate (7%; p less than .05) and aortic pressure (14%; p less than .001). Pulmonary arterial pressure and pulmonary wedge pressure were unchanged by diltiazem. Diltiazem did not prevent the increase in heart rate or in aortic or wedge pressure associated with handgrip. Diltiazem prolonged atrioventricular conduction from 0.18 +/- 0.03 to 0.20 +/- 0.03 sec (p less than .001). Compared with control values, nitroglycerin reduced aortic pressure (14%; p less than .005), pulmonary arterial pressure (38%; p less than .001), and pulmonary wedge pressure (42%; p less than .005). Heart rate was unchanged. The constriction (20%) in lumen area of normal coronary arterial segments during handgrip was effectively prevented by infusion of diltiazem (1%; p less than .001). Nitroglycerin produced a significantly greater increase (20%) in diameter of normal coronary arterial segments than diltiazem (3%; p less than .001) and tended to have a more favorable effect than diltiazem on stenosis minimum area and flow resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Left ventricular function before and following surgical treatment of mitral valve disease

Nineteen patients with mitral valve disease were studied before and a mean 11 months +/- 9 months following valve replacement or reconstruction, which resulted in good postoperative valve function. Biplane left ventricular angiography and pressures were utilized to determine end-diastolic volume/M. (EDV), end-systolic volume/M. (ESV), ejection fraction (EF), left ventricular mass/M. (LVM), and stroke work/M. (SW). There were 19 patients--six with mitral stenosis (MS), six with mitral stenosis and regurgitation (MS + MR), and seven with mitral regurgitation (MR). Those with MS and MS + MR preoperatively had no significant change in left ventricular end-diastolic pressure (LVEDP), EDV, ESV, LVM, or EF following surgery. Patients with MR had a significant reduction in LVEDP, EDV, SV, and SW. More importantly, the EF fell in four of these seven patients and LVM did not decrease following surgery. It is concluded that surgical treatment for MS and MS + MR had little effect on left ventricular performance. Following surgical treatment for MR, reduction in EDV is not associated with reduction in LVM, and frequently left ventricular performance deteriorates as judged by the EF.

Immediate effect of contrast medium injection on left ventricular volumes and ejection fraction. A study using metallic epicardial markers.

The immediate effect of contrast medium injection on left ventricular (LV) volume, stroke volume (SV) and ejection fraction (EF) was evaluated from postoperative LV biplane cineangiograms of 10 patients with 4-6 epicardial markers placed at the time of coronary artery surgery. After calibrating marker distances with respect to volume (r = 0.97-0.99) over one cardiac cycle for each patient, regression equations were used to compute LV volume from marker measurements for beats prior to, during and following injection. End-diastolic volumes (EDV) prior to injection ranged from 93-263 ml and did not change significantly with injection. End-systolic volumes (ESV) showed a mean decrease of 7.3 ml by beat 7 following injection; this was of borderline significance. Similarly, there was no significant change of SV or EF until beat 7 when there were small but significant increases of 6.4 ml and 0.04, respectively. The injection of moderate amounts of contrast in man does not cause significant changes in LV volume or EF through the sixth postinjection beat.

Postinfarction angina: results of early revascularization.

To assess the efficacy of surgical revascularization for postinfarction angina within 30 days of acute infarction, the clinical course of 103 patients treated surgically from January 1979 to July 1982 was reviewed. There were 84 men (82%) and 19 women (18%) with a mean age of 58 years (range 34 to 80). Group A (11 patients) underwent surgery within 24 hours of infarction, Group B (21 patients) within 7 days and Group C (71 patients) within 30 days. Eighty-four patients (82%) had subendocardial infarctions and 19 patients (18%) had transmural infarction. Transmural infarction was more common in patients in Group A (36%) than in those in either Group B (19%) or Group C (15%). There were two deaths, both in Group C (1.9%), within 30 days of surgery. The use of intraaortic balloon or inotropic support and the occurrence of major arrhythmias or perioperative infarction was noted in 30 patients (29%) (64% in Group A, 33% in Group B and 18% in Group C). The average time in the intensive care unit was 3.2 days, with an average total hospital stay after surgery of 8.3 days. Late follow-up (mean 15.4 months, range 1 to 39) is complete for 97 patients (97%). There were no late myocardial infarctions and 93 patients (96%) were essentially free of angina. The only late death (1.0%) was caused by septicemia from delayed sternal wound infection. This study suggests that myocardial revascularization within the first 30 days after myocardial infarction can be accomplished with an acceptable operative mortality in selected patients with postinfarction angina refractory to medical management.