The relationship between regional myocardial perfusion at rest and arteriographic lesions in patients with coronary atherosclerosis.

Measurements of mean left ventricular (LV) and regional myocardial blood flow rates were made at rest in 161 patients with 133Xe and a multiplecrystal scintillation camera. Myocardial perfusion rates were correlated with assessments of the degree of coronary artery disease made from the arteriograms obtained during the same studies. In patients with normal coronary arteries without heart failure, the presence of hypertension, aortic stenosis, or aortic insufficiency was not associated with changes in mean LV perfusion from the control value of 61+/-7 ml/100 g-min. However, mean LV perfusion was significantly reduced in patients with normal coronary arteries who had cariomyopathy and impaired ventricular performance. Mean LV perfusion was not significantly different from control values in patients with "mild" coronary artery disease (less than 50% obstruction) or in patients with significant isolated disease (greater than 50% obstruction) of the left anterior descending (lad) artery. Significant reductions in mean LV perfusion were found in patients with greater than 50% obstruction of two coronary arteries (LAD + right or LAD + circumflex) and in patients with triple-vessel disease. The average perfusion rate for regions distal to LAD obstructions in patients with isolated LAD disease was not lower than the LAD perfusion in control patients, but was significantly reduced in patients with LAD + right coronary artery disease (43+/-14 ml/100 g-min). In the latter group average perfusion distal to the LAD lesion was significantly lower than the average regional perfusion rate for the remainder of the LV. However, the mean blood flow rate for the remainder of the LV was also significantly lower than control values despite the lack of significant circumflex disease. The data demonstrate that the presence of radiographically "mild" or significant isolated LAD coronary disease is not associated with reductions in mean LV perfusion at rest, but that mean LV perfusion is reduced in the presence of significant disease of two or three coronary artieries. None of the patients experienced angina during the resting studies and most had clinical evidence of ventricular failure. The observation of depressed LV perfusion in this group, as in the patients with cardiomyopathy, raises the possibility that a lowered resting blood supply may be adequate for a reduced level of performance of a diseased ventricle. The lack of selective reductions of regional perfusion at rest in the majority of the patients with LAD lesions suggests that regional myocardial blood flow must be measured during an intervention which increases myocardial oxygen consumption in order to assess the physiological significance of lesions which are observed at coronary arteriography.

Persistent mismatch repair deficiency following targeted correction of hMLH1.

The use of gene therapy to correct mutated or lost gene function for the treatment of human cancers has been an active, yet problematic area of biomedical research. Many technical difficulties, including efficient tissue-specific delivery, integration site specificity and general toxicity, are being addressed. Little is known, however, about the genetic and phenotypic stability that accompanies a successful gene-specific targeting event in a cancer cell. This question was addressed following the creation of a colon cancer cell line in which a mutated hMLH1 gene was corrected via targeted homologous recombination. This correction resulted in the expression of wild-type hMLH1 protein, restoration of the hPMS2 protein and mismatch repair (MMR) proficiency. One of two hMLH1-corrected clones, however, was found to retain defects in MMR activity. These cells continued to express the corrected hMLH1 protein, but had lost expression of another MMR protein, hMSH6. DNA sequence analysis of the hMSH6 gene revealed biallelic expansions of a cytosine repeat region in exon 5 that result in frameshifts leading to premature stop codons. These findings suggest that, similar to acquired drug resistance, the presence of genetically heterogeneous cancer cell populations or acquisition of compensatory mutations can result in 'resistance' to gene replacement therapy.

Influence of pre-PTCA strategy and initial PTCA result in patients with multivessel disease: the Bypass Angioplasty Revascularization Investigation (BARI).

BACKGROUND: In PTCA patients with multivessel coronary artery disease, incomplete revascularization (IR) is the result of both pre-PTCA strategy and initial lesion outcome. The unique contribution of these components on long-term patient outcome is uncertain. METHODS AND RESULTS: From the Bypass Angioplasty Revascularization Investigation (BARI), 2047 patients who underwent first-time PTCA were evaluated. Before enrollment, all significant lesions were assessed by the PTCA operator for clinical importance and intention to dilate. Complete revascularization (CR) was defined as successful dilatation of all clinically relevant lesions. Planned CR was indicated in 65% of all patients. More lesions were intended for PTCA in these patients compared with those with planned IR (2.8 versus 2.1). Successful dilatation of all intended lesions occurred in 45% of patients with planned CR versus 56% with planned IR (P<0. 001). In multivariable analysis, planned IR (versus planned CR), initial lesions attempted (not all versus all intended lesions attempted), and initial lesion outcome (not all versus all attempted lesions successful) were unrelated to 5-year risk of cardiac death or death/myocardial infarction but were all independently related to risk of CABG. CONCLUSIONS: Overall, a pre-PTCA strategy of IR in BARI-like patients appears comparable to a strategy of CR except for a higher need for CABG. Whether the use of new devices may attenuate the elevated risk of CABG in patients with multivessel disease and planned IR remains to be determined.

Kawasaki syndrome in an adult: endomyocardial histology and ventricular function during acute and recovery phases of illness.

Kawasaki syndrome, an acute systemic inflammatory illness of unknown origin usually affecting children, may develop into a serious illness complicated by coronary artery aneurysms or myocarditis. This report describes an adult with Kawasaki syndrome studied by right ventricular endomyocardial biopsy and cardiac catheterization during the acute and recovery phases of illness. The initial biopsy specimen showed acute myocarditis and was associated with hemodynamic evidence of biventricular dysfunction, a severely depressed left ventricular ejection fraction and global hypokinesia. With time, there was spontaneous and rapid resolution of the inflammatory cell infiltrate with concurrent return to normal myocardial function. Right ventricular endomyocardial biopsy studies early in the course of the cardiac disease associated with Kawasaki syndrome may correlate with ventricular function and may be useful for monitoring immunosuppressive therapy in patients with this syndrome.

Cardiopulmonary exercise testing. The clinical value of gas exchange data.

Cardiopulmonary exercise testing is a noninvasive tool whose clinical value is not yet widely recognized. The technique involves breath-by-breath measurement of respiratory gas exchange during a symptom-limited exercise test, with determination of maximal oxygen uptake and anaerobic threshold. These measurements serve as objective, reproducible indices of exercise capacity that can be applied to the management of various clinical problems. In addition, by permitting simultaneous assessment of circulatory and ventilatory reserves, the test can be especially helpful in the differential diagnosis of exertional dyspnea and fatigue. This paper reviews the physiology of gas exchange, the limitations of standard exercise tests, and the methodology and clinical applications of cardiopulmonary exercise testing.

Percutaneous transluminal coronary angioplasty of a coronary artery with a total occlusion.

Percutaneous transluminal coronary angioplasty has become an accepted therapeutic modality for patients with coronary artery disease. Until the present, its use has been restricted to vessels that are subtotally obstructed. We recently successfully utilized coronary angioplasty in a patient with a totally occluded coronary artery. The experience is described and criteria proposed for the selection of patients with totally obstructed coronary arteries for coronary angioplasty.

Improved exercise ejection fraction with long-term prazosin therapy in patients with heart failure.

To study the effect of prazosin therapy on left ventricular function in patients with chronic stable heart failure, first pass radionuclide angiography at rest and during exercise was performed in 15 patients before the administration of prazosin and after seven to 12 weeks of prazosin therapy. There was no significant change in resting ejection fraction before and during prazosin therapy (36 +/- 14 per cent versus 37 +/- 14 per cent) (mean +/- standard deviation). However, exercise ejection fraction increased from 34 +/- 14 per cent to 42 +/- 17 per cent (p less than 0.01). The difference in ejection fraction from rest to exercise (ejection fraction response) changed significantly from -2 +/- 6 per cent before prazosin therapy to +5 +/- 7 per cent during prazosin therapy (p less than 0.01). Exercise duration increased from 368 +/- 82 seconds to 476 +/- 82 seconds (p less than 0.01). Total work capacity measured in kilojoules increased from 12.6 +/- 8.3 to 18.6 +/- 10.4 (p less than 0.01). The improved ejection fraction response during prazosin therapy correlated with the improved work capacity (r = 0.69, p less than 0.01) and exercise duration (p = 0.59, p less than 0.05). This improvement occurred despite a significant weight gain with prazosin from 72.2 +/- 20.8 kg to 73.5 +/- 20.8 kg (p less than 0.01). These data suggest that long-term prazosin therapy is effective in the treatment of heart failure. However, the beneficial effects of prazosin, an alpha 1 blocking agent, may be evident only during exercise.

Percutaneous intraaortic balloon insertion.

A new single chambered percutaneous intraaortic balloon has been constructed around a central guidewire. The balloon can be wrapped around the guidewire, enabling its insertion into the femoral artery through a 12F sheath inserted with the conventional Seldinger technique. Percutaneous intraaortic balloon insertion has been performed in 27 patients (mean age 58 years) for a variety of medical and surgical indications. Percutaneous balloons could not be advanced into the aorta in two patients (7.4 percent) with severe bilateral aortoiliac occlusive disease. In all 25 patients undergoing intraaortic balloon pumping satisfactory circulatory support was achieved, and 21 (84 percent) of the patients survived to be discharged from the hospital. The mean duration of intraaortic balloon pumping was 3.5 days. Percutaneous intraaortic balloon insertion requires less than 5 minutes and has been successfully performed in the cardiac catheterization laboratory, coronary care unit, operating room and recovery room. After direct balloon removal, external pressure was applied for 30 minutes. No patient experienced hematoma of the groin, aortic dissection, compromised distal pulses or late wound complications. Percutaneous balloon insertion permits the rapid institution of circulatory support and broadens the medical and surgical applications of intraaortic balloon pumping.

Method for recording electrical activity of the sinoatrial node and automatic atrial foci during cardiac catheterization in human subjects.

A method for recording electrical activity of the sinoatrial (S-A) node and automatic atrial foci in human subjects is described. To record S-A nodal electrograms, an electrode catheter was inserted percutaneously into the femoral vein and advanced under fluoroscopic control to the superior vena caval-right atrial junction. The distal terminal of the catheter was placed in the area of the S-A node and the proximal terminal on the free right atrial wall or in the right atrial lumen. Polarity was reversed from the conventional electrocardiographic recording; high amplification (about 100 microV/cm) and selective filters (0.1 to 20 hertz) were used. S-A nodal electrograms recorded with this method in human subjects were similar to electrograms obtained previously from the dog and rabbit and revealed negatively directed diastolic and upstroke slopes preceding the P wave of the electrocardiogram. Sinoatrial conduction time measured from the S-A nodal electrograms in 15 cases was 34.9 +/- 2.1 ms(mean +/- standard error of the mean) for a sinus cycle length of 736.4 +/- 38.6 ms. The coronary sinus electrograms in a patient with coronary sinus rhythm were recorded by the same technique except that the distal terminal of the catheter was placed at the coronary sinus ostium. A negatively directed diastolic slope preceding the P wave was consistently recorded. This method for recording electrograms of the S-A node and ectopic automatic atrial foci should prove useful in (1) assessment of both normal and abnormal S-A nodal function, (2) direct determination of conduction time from the S-A nodal pacemaker to the atrium, and (3) localization of automatic atrial foci.

Validation of the angiographic accuracy of digital left ventriculography.

Digital subtraction angiography enhances the contrast to background signal, enabling the performance of angiography with reduced doses of contrast medium. The objectives of the present study were (1) to validate the accuracy of digital left ventriculography for measurement of left ventricular volumes and segmental contraction; and (2) to compare the hemodynamic effects resulting from low-and high-dose intraventricular contrast injections. Twenty-eight patients underwent digital left ventriculography, performed by intraventricular injection of 7 ml of contrast medium diluted in saline solution, followed by conventional cineangiography of the left ventricle performed with 45 ml of undiluted contrast medium. Left ventricular volumes calculated from digital ventriculograms correlated well with volumes calculated from conventional ventriculograms: end-diastolic volume (r = 0.97, standard error of estimate [SEE] 23.4 ml; end-systolic volume (r = 0.97, SEE 15.4 ml); stroke volume (r = 0.95, SEE 14.7 ml); and ejection fraction (r = 0.97, SEE 3.8%). Segmental left ventricular contraction, measured as percent chordal shortening of hemiaxes, correlated moderately well (r = 0.81, SEE 11.5%). After injection of undiluted contrast medium, left ventricular systolic pressure decreased (133 +/- 31 to 123.5 +/- 27 mm Hg; p less than 0.01) and left ventricular end-diastolic pressure increased (12.0 +/- 7 to 16.9 +/- 10 mm Hg; p less than 0.001). Left ventricular systolic and end-diastolic pressures did not change significantly after injection of diluted contrast medium, and patients had no discomfort. Thus, digital subtraction angiography permits the performance of left ventriculography with markedly reduced doses of contrast medium, obviating the hemodynamic effects resulting from injection of conventional doses of contrast medium. This new approach to left ventriculography provides high resolution ventriculograms for accurate measurement of left ventricular volumes, stroke volume, and ejection fraction.

Measurement of regional myocardial blood flow in man: description and critique of the method using xenon-133 and a scintillation camera.

A method has been devised to measure regional myocardial blood flow in man. The approach consists of selective injection of xenon-133 into a coronary artery and the external monitoring of radioisotope washout curves from multiple areas of the myocardium with a multiple crystal scintillation camera. Rate constants of isotope washout are calculated using a monoexponential model, and the capillary blood flow rates in multiple regions of the heart are calculated by the Kety formula. The pattern of perfusion rates is related to the coronary arteriogram obtained in the same study. Myocardial perfusion patterns obtained in patients with and without coronary artery disease and during atrial pacing are given, as well as examples of results obtained in myocardial aneurysms, in regions of ischemic myocardium supplied by collateral vessels and after tracer injection into an aortocoronary bypass graft. Advantages of the method are discussed along with limitations related to the tracer, the scintillation camera, the form of mathematical analysis and the three dimensional nature of the heart.

Studies of regional myocardial blood flow: results in patients with left anterior descending coronary artery disease.

Measurements of regional myocardial blood flow have been performed rapidly and safely in man at the time of coronary arteriography. Xenon-133 was injected into the coronary artery and estimates of myocardial capillary perfusion were made by computer analysis of the multiple precordial tracer washout curves recorded with a scintillation camera. Blood flow rates/100 g/min in different areas of the heart were calculated by the Schmidt-Kety formula, using an assumed partition coefficient, and were related to the coronary vascular lesions by landmarks provided by the arteriograms. The flow significance of lesions was assessed by making measurements at rest and during interventions that increase coronary blood flow. Perfusion was also estimated in areas supplied by collateral vessels, and regions of scar were detected from the initial distribution of peak tracer activity. In patients with less than 50% obstructions apparent on coronary arteriograms and in those with greater than 50% isolated left anterior descending lesions average mean left ventricular (LV) myocardial perfusion values were not reduced below values found in patients with normal coronary arteries and normal cardiac function. However, in patients with significant two-vessel disease (LAD + right, LAD + circ) mean LV perfusion was significantly reduced. Average regional myocardial perfusion distal to significant lesions was not selectively reduced below the remainder of the ventricle unless the lesions were 100% obstructions. However, both total and distal regional myocardial perfusion increased less in 12 patients with greater than 50% lesions than in 12 others with normal arteriograms or less than 50% lesions. Subnormal flow responses in all of the former group were associated with angina pectoris compared with no angina in the latter. The studies indicate the potential utility of the measurements of regional myocardial blood flow in the evaluation of patients with ischemic heart disease who are potential candidates for myocardial revascularization procedures.

Monoclonal antibody identification of mononuclear cells in endomyocardial biopsy specimens from a patient with rheumatic carditis.

A 17-year-old woman with rheumatic carditis underwent endomyocardial biopsy both prior to and following treatment with prednisone and aspirin. Frozen sections from the endomyocardial biopsy specimens were studied with monoclonal antibodies by an indirect immunofluorescence technique to define the composition of the inflammatory infiltrate in the myocardium and to determine whether the composition of the infiltrate is distinctive and diagnostically useful. The specimen from the initial biopsy contained a heterogeneous infiltrate composed of T lymphocytes, macrophages, B lymphocytes, and mast cells. T lymphocytes predominated, and the ratio of T-helper to T-cytotoxic/suppressor cells was 2.0. Following treatment the overall cellularity of the infiltrate was diminished, but the infiltrate remained heterogeneous; T cells predominated, and the T-helper to T-cytotoxic/suppressor ratio was reversed, to 0.59. The composition of the inflammatory infiltrate in this case of rheumatic carditis distinguishes it immunologically from other "idiopathic," presumably virus-associated, forms of myocarditis.

Effects of pulsatile and nonpulsatile coronary perfusion on performance of the canine left ventricle.

This study compares the effect of pulsatile (Group C, Fib/P) and nonpulsatile (Group B, Fib/NP) coronary perfusion on myocardial performance during 2 hours of normothermic ventricular fibrillation. Group A (BH/NP), used as a base-line observation, consisted of 2 hours of nonpulsatile coronary perfusion in beating hearts. The assessment of ventricular performance included diastolic ventricular compliance, myocardial oxygen consumption and lactate extraction, regional myocardial blood flow, and histology. After 120 minutes of ventricular fibrillation, Group C showed normal ventricular diastolic compliance as compared to a 50 per cent decrease in Group B (p less than 0.01). Myocardial oxygen consumption was not significantly different from that in Group B. Because of a 70 per cent increase in oxygen extraction above Group B (p less than 0.05), total left ventricular myocardial blood flow was reduced (103 +/- 23 versus 260 +/- 36 ml. per 100 Gm. per minute, p less than 0.05) and had near-constant resistance. Lactate extraction was significantly greater and more stable as compared to Group B (9.28 +/- 1.33 versus 1.8 +/- 1.08, p less than 0.05). Left ventricular endocardial/epicardial flow ratio was greater in Group C (1.21 +/- 0.08 versus 1.06 +/- 0.06, p less than 0.05). Minimal subendocardial histologic changes were present as compared to the marked patchy subendocardial ischemic changes seen in Group B. The results demonstrate that the addition of pulsatile flow to coronary perfusion minimized the deleterious effects of prolonged ventricular fibrillation on myocardial performance.

Serological evidence of Hantaan virus infection in the United States.

We found low titers of fluorescent antibodies against Hantaan virus, the etiologic agent of Korean hemorrhagic fever, in sera from 7 of 1,035 patients with febrile illnesses of unknown origin and from 6 of 664 blood donors in the United States. All but 1 of these individuals possessed neutralizing antibodies against Hantaan virus. This was a 31-year-old research technician who had worked with laboratory rodents with virus-induced tumors, but had not traveled abroad, suggesting that infection with Hantaan virus or a closely related agent was locally acquired. However, the precise source of his infection remains unclear.

Deletion of p53 in human mammary epithelial cells causes chromosomal instability and altered therapeutic response.

The TP53 tumor suppressor gene is the most commonly mutated gene in human cancers. To evaluate the biological and clinical relevance of p53 loss, human somatic cell gene targeting was used to delete the TP53 gene in the non-tumorigenic epithelial cell line, MCF-10A. In all four p53-/- clones generated, cells acquired the capability for epidermal growth factor-independent growth and were defective in appropriate downstream signaling and cell cycle checkpoints in response to DNA damage. Interestingly, p53 loss induced chromosomal instability leading to features of transformation and the selection of clones with varying phenotypes. For example, p53-deficient clones were heterogeneous in their capacity for anchorage-independent growth and invasion. In addition, and of clinical importance, the cohort of p53-null clones showed sensitivity to chemotherapeutic interventions that varied depending not only on the type of chemotherapeutic agent, but also on the treatment schedule. In conclusion, deletion of the TP53 gene from MCF-10A cells eliminated p53 functions, as well as produced p53-/- clones with varying phenotypes possibly stemming from the distinct chromosomal changes observed. Such a model system will be useful to further understand the cancer-specific phenotypic changes that accompany p53 loss, as well as help to provide future treatment strategies for human malignancies that harbor aberrant p53.