Showing papers in "Circulation in 1987"

Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction.

Abstract: Impairment of left ventricular function is the major predictor of mortality after acute myocardial infarction, but it is not known whether this is best described by ejection fraction or by end-systolic or end-diastolic volume. We measured volumes, ejection fractions, and severity of coronary arterial occlusions and stenoses in 605 male patients under 60 years of age at 1 to 2 months after a first (n = 443) or recurrent (n = 162) myocardial infarction and followed these patients for a mean of 78 months for survivors (range 15 to 165 months). There were 101 cardiac deaths, 71 (70%) of which were sudden (instantaneous or found dead). Multivariate analysis with log rank testing and the Cox proportional hazards model showed that end-systolic volume (chi 2 = 82.9) had greater predictive value for survival than end-diastolic volume (chi 2 = 59.0) or ejection fraction (chi 2 = 46.6), whereas stepwise analysis showed that once the relationship between survival and end-systolic volume had been fitted, there was no additional significant predictive information in either end-diastolic volume or ejection fraction. Severity of coronary occlusions and stenoses showed additional prediction of only borderline significance (p = .04 in one analysis), but continued cigarette smoking did remain an independent risk factor after stepwise analysis. For a subset of patients (n = 200) who had taken part in a randomized trial of coronary artery surgery after recovery from infarction, surgical "intention to treat" showed no predictive value.(ABSTRACT TRUNCATED AT 250 WORDS)

Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: A comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge.

Abstract: Intravenous administration of 80 mg of recombinant tissue plasminogen activator (rt-PA, 40, 20, and 20 mg in successive hours) and streptokinase (SK, 1.5 million units over 1 hr) was compared in a double-blind, randomized trial in 290 patients with evolving acute myocardial infarction. These patients entered the trial within 7 hr of the onset of symptoms and underwent baseline coronary arteriography before thrombolytic therapy was instituted. Ninety minutes after the start of thrombolytic therapy, occluded infarct-related arteries had opened in 62% of 113 patients in the rt-PA and 31% of 119 patients in the SK group (p less than .001). Twice as many occluded infarct-related arteries opened after rt-PA compared with SK at the time of each of seven angiograms obtained during the first 90 min after commencing thrombolytic therapy. Regardless of the time from onset of symptoms to treatment, more arteries were opened after rt-PA than SK. The reduction in circulating fibrinogen and plasminogen and the increase in circulating fibrin split products at 3 and 24 hr were significantly less in patients treated with rt-PA than in those treated with SK (p less than .001). The occurrence of bleeding events, administration of blood transfusions, and reocclusion of the infarct-related artery was comparable in the two groups. Thus, in patients with acute myocardial infarction, rt-PA elicited reperfusion in twice as many occluded infarct-related arteries as compared with SK at each of seven serial observations during the first 90 min after onset of treatment.

Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study.

Abstract: A cohort of 2270 white women, aged 40-69 years at baseline, were followed for an average of 8.5 years in the Lipid Research Clinics Program Follow-up Study. There were 44 deaths due to cardiovascular disease among the 1677 nonusers of estrogens and six cardiovascular disease deaths among the 593 estrogen users. The age-adjusted relative risk (RR) of cardiovascular disease deaths in users compared with nonusers was 0.34 (95% confidence limits 0.12 to 0.81). After multivariable adjustment for potential confounding factors (age, blood pressure, and smoking), the estimated RR for estrogen use was 0.37 (95% confidence limits 0.16 to 0.88). Analyses were done to explore whether these results could be due to selection bias for estrogen use. However, the prevalence of cardiovascular disease at baseline was slightly higher in estrogen users (12%) than in nonusers (10%); furthermore, the exclusion of all women with prevalent cardiovascular disease at baseline did not alter the apparent protective effect of estrogen use on cardiovascular disease mortality (RR = 0.42, 95% confidence limits 0.13 to 1.10). Additional analyses examining the complex association between estrogen use, lipoprotein levels, and cardiovascular disease mortality suggest that the protective effect of estrogen is substantially mediated through increased high-density lipoprotein levels.

Color Doppler assessment of mitral regurgitation with orthogonal planes.

Abstract: We evaluated 147 patients with adequate color Doppler and angiographic studies for mitral regurgitation. Sixty-five patients had no mitral regurgitation by both color Doppler and angiography and 82 patients had mitral regurgitation by both techniques. Thus the sensitivity and specificity of color Doppler for the detection of mitral regurgitation was 100%. Three two-dimensional echocardiographic planes (parasternal long and short axis, apical four-chamber view) were used to analyze variables of the mitral regurgitant jet signals in the left atrium. The best correlation with angiography was obtained when the regurgitant jet area (RJA) (maximum or average from three planes) expressed as a percentage of the left atrial area (LAA) obtained in the same plane as the maximum regurgitant area was considered. The maximum RJA/LAA was under 20% in 34 of 36 patients with angiographic grade I mitral regurgitation, between 20% and 40% in 17 of 18 patients with grade II mitral regurgitation, and over 40% in 26 of 28 patients with severe mitral regurgitation. Maximum RJA/LAA also correlated with angiographic regurgitant fractions (r = .78) obtained in 21 of 40 patients in normal sinus rhythm and with no evidence of associated aortic regurgitation. Other variables of the regurgitant jet such as maximal linear and transverse dimensions, maximal area, or maximal area expressed as a percentage of the LAA in one or two planes correlated less well with angiography. Color Doppler is a useful noninvasive technique that is not only highly sensitive and specific in the identification of mitral regurgitation but also provides accurate estimation of its severity.

Circadian variation in the frequency of sudden cardiac death.

Abstract: To determine whether sudden cardiac death exhibits a circadian rhythm similar to that recently demonstrated for nonfatal myocardial infarction, we analyzed the time of day of sudden cardiac death as indicated by death certificates of 2203 individuals dying out of the hospital in Massachusetts in 1983. The data reveal a prominent circadian variation of sudden cardiac death, with a low incidence during the night and an increased incidence from 7 to 11 A.M. The pattern is remarkably similar to that reported for nonfatal myocardial infarction and episodes of myocardial ischemia. The finding that the frequency of sudden cardiac death is increased in the morning is compatible with hypotheses that sudden cardiac death results from ischemia or from a primary arrhythmic event. Further study of the physiologic changes occurring in the morning may provide new information supporting or refuting these hypotheses, thereby leading to increased understanding and possible prevention of sudden cardiac death.

Improved sex-specific criteria of left ventricular hypertrophy for clinical and computer interpretation of electrocardiograms: validation with autopsy findings.

Abstract: In a previous study of 543 patients we developed, using echocardiographic left ventricular mass as the reference standard, two new sets of criteria that improve the electrocardiographic diagnosis of left ventricular hypertrophy (LVH) One set of criteria, which is suitable for routine clinical use, detects LVH when the sum of voltage in RaVL + SV3 (Cornell voltage) exceeds 28 mV in men and 20 mV in women The second set of criteria, suitable for use in interpretation of the computerized electrocardiogram, uses logistic regression models based on electrocardiographic and demographic variables with independent predictive value for LVH, with separate equations for patients in sinus rhythm and atrial fibrillation To test these criteria prospectively with use of a different reference standard, antemortem electrocardiograms were compared with left ventricular muscle mass measured at autopsy in 135 patients Sensitivity of standard Sokolow-Lyon voltage (SLV) criteria (SV1 + RV5 or RV6 greater than 35 mV) for LVH was only 22%, but specificity was 100% The Cornell voltage criteria improved sensitivity to 42%, while maintaining high specificity at 96% Higher sensitivity (62%) was achieved by use of the new regression criteria, with a specificity of 92% Overall test accuracy was 60% for SLV criteria, 68% for the Cornell voltage criteria, and 77% for the new regression criteria (p less than 005 vs SLV) We conclude that the Cornell voltage criteria improve the sensitivity of the electrocardiogram for detection of LVH and are easily applicable in clinical practice(ABSTRACT TRUNCATED AT 250 WORDS)

Development of coronary artery disease in cardiac transplant patients receiving immunosuppressive therapy with cyclosporine and prednisone.

Abstract: Coronary artery disease (CAD) has been shown in previous uncontrolled studies to be a limiting factor to long-term survival in patients undergoing cardiac transplantation and who were taking conventional immunosuppressive agents. To study the development of CAD after cardiac transplantation in patients taking the newer immunosuppressive agent cyclosporine, we prospectively performed yearly coronary arteriography on all eligible transplantation patients (first year, 57 patients; second year, 30 patients; third year, 14 patients). The prevalence of CAD by life table analysis was 18% at 1 year, 27% at 2 years, and 44% at 3 years. The occurrence of two or more major rejection episodes was associated (p less than .005) with the development of CAD. In two patients who died of CAD, coronary artery histology revealed subintimal inflammatory cellular infiltration in some lesions. These data demonstrate that the prevalence of CAD rises progressively over time and immunologic factors may be important in its development.

Circadian variation of transient myocardial ischemia in patients with coronary artery disease.

Abstract: To examine whether a significant circadian variation of transient myocardial ischemia exists and to better understand the character of such variation, 32 patients with chronic stable symptoms of coronary artery disease underwent one or more days of ambulatory monitoring of ischemic ST segment changes during daily life. A total of 251 episodes of ischemic ST segment depression occurred in 24 (75%) of the 32 patients with a median duration of 5 min (range 1 to 253). A significant circadian increase in ischemic activity was found with 39% of episodes and 46% of total ischemic time occurring between 6 A.M. and 12 P.M. (p less than .05 and p = .02, respectively). In 21 patients with ST segment depression during the 6 hr after waking and the 6 hr before sleep, 68% of episodes occurred in the morning compared with 32% in the evening. There were no significant differences in heart rate at onset, heart rate at 1 min before onset, and activity score associated with ST segment depression. The proportion of minutes showing ST segment depression when the heart rate was above the lowest rate associated with ST segment depression was significantly greater in the morning compared with the evening (26% vs 15%; p = .03). Thus the early morning increase in ST segment depression does not appear to be explained by differences in extrinsic activity and/or stress measured by physical activity score and heart rate response. More importantly, this phenomenon is often ignored by the usual patterns of drug administration for angina.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative influence of load versus inotropic states on indexes of ventricular contractility: experimental and theoretical analysis based on pressure-volume relationships.

Abstract: We examined the quantitative influence of carefully controlled alterations in end-diastolic volume and afterload resistance on multiple simultaneously determined ejection and isovolumetric phase indexes of left ventricular contractile function in 23 isolated supported canine ventricles. The influence of load change on each index was compared with its sensitivity to inotropic stimulation, and this sensitivity was in turn contrasted to the response of the end-systolic pressure-volume relationship (ESPVR). Experimental data demonstrated various degrees of load sensitivity among the indexes, with a generally curvilinear relationship between load and index response for both preload and afterload alterations. The curvilinear nature of these relationships meant that over a select range of loading, many indexes demonstrated relative load independence. They also often displayed greater sensitivity to inotropic change than the ESPVR, and both factors help explain their enduring clinical utility. To further explore the influence of load and contractile state on several of the indexes, we developed a theoretical analysis, using variables common to pressure-volume relationships, in which these dependencies could be derived. The theoretical models fit very well with the experimental data, and reaffirmed the frequently curvilinear nature of the relationships. We conclude that while many clinical indexes of ventricular contractile function show significant load dependence, the information they provide can be reasonably interpreted within defined ranges of load and inotropic alteration. Any advantage of the ESPVR will derive not from the magnitude of its response to inotropic change, which is smaller than most other indexes, but from its relative insensitivity to load alteration over a wider range of load.

Deficient production of cyclic AMP: Pharmacologic evidence of an important cause of contractile dysfunction in patients with end-stage heart failure

Abstract: We studied the effects of different classes of inotropic drugs on human working myocardium in vitro that was isolated from the hearts of patients with end-stage heart failure, and compared the responses to these drugs with those noted in muscles from nonfailing control hearts. Although peak isometric force generated in response to increased extracellular calcium reached control levels in the muscles from patients with heart failure, the time course of contraction and rate of relaxation were greatly prolonged. The inotropic effectiveness of the beta-adrenergic agonist isoproterenol and the phosphodiesterase inhibitors milrinone, caffeine, and isobutylmethylxanthine was markedly reduced in muscles from the patients with heart failure. In contrast, the effectiveness of inotropic stimulation with acetylstrophanthidin and the adenylate cyclase activator forskolin was preserved. After a minimally effective dose of forskolin was given to elevate intracellular cyclic AMP levels, the inotropic responses of muscles from the failing hearts to phosphodiesterase inhibitors were markedly potentiated. These data indicate that an abnormality in cyclic AMP production may be a fundamental defect present in patients with end-stage heart failure that can markedly diminish the effectiveness of agents that depend on generation of this nucleotide for production of a positive inotropic effect.

Limitation of myocardial infarct expansion by reperfusion independent of myocardial salvage.

Abstract: Very early reperfusion after coronary occlusion can reduce infarct size and preserve left ventricular function. Whether later reperfusion is of benefit is unclear. We studied the effect of very early reperfusion with myocardial salvage and "late" reperfusion without myocardial salvage on infarct expansion and aneurysm formation. Sixty-eight rats underwent left coronary artery ligation and were randomized to 30 min reperfusion, 2 hr reperfusion, or permanent coronary artery ligation. The animals were killed and the hearts examined at 2 weeks. Thirty minute reperfusion reduced infarct size, extent of transmurality, and infarct expansion. Two hour reperfusion reduced neither infarct size nor transmurality but inhibited infarct expansion. The results of this study in the rat preparation suggest a beneficial effect of "late" reperfusion on infarct expansion independent of myocardial salvage. If these results are confirmed in human beings, the period after myocardial infarction during which a patient can be considered for thrombolytic therapy or reperfusion by percutaneous transluminal coronary angioplasty could be greatly prolonged.

Nonsurgical closure of patent ductus arteriosus: clinical application of the Rashkind PDA Occluder System.

Abstract: The first successful application of a transcatheter closure technique for patent ductus arteriosus (PDA) suitable for use in infants and children was performed by us in 1977. Since that time, there has been continued improvement and simplification of the equipment as well as in the implantation technique. Following a Food and Drug Administration protocol, a multicenter study was conducted to test the safety and effectiveness of this interventional method. The clinical results from three major regional test centers (Philadelphia, Houston, and New Haven) are presented. One hundred forty-six patients from a test population of 156 were treated for PDA with use of the Rashkind PDA Occluder Systems. Successful closure was accomplished in 94 (66%) of the total cases. Ten patients (7%) retained residual ductal murmurs despite correct placement of the occlusion devices; five additional patients (3%) were considered failures due to the presence of abnormal Doppler flow patterns after the procedure. Postrelease embolizations occurred in 19 (15%) instances. One patient required emergency surgical intervention after attempted retrieval of an embolized occluder. With the improvements in the manufacturing of the double-disk occluder systems as well as the perfection of the transvenous delivery technique, the incidences of closure failure and postrelease complications have decreased. Since January 1984, 78% of all transcatheter closure attempts were successful, with 10% embolization.

Automated quantitative coronary arteriography: morphologic and physiologic validation in vivo of a rapid digital angiographic method.

Abstract: Quantitative coronary arteriography has been shown to be useful in assessing the extent of coronary disease, its functional significance, and its response to therapeutic interventions. Most current methods rely either on hand-drawn arterial contours or automatic edge-detection algorithms applied to 35 mm cineangiograms. To assess the performance in vivo of a new, fully automatic, rapid coronary quantitation program, dogs were instrumented with precision-drilled, plastic cylinders to create intraluminal stenoses in the left anterior descending and/or circumflex arteries, as well as with high-fidelity micromanometers and electromagnetic flow probes. Stenosis diameters ranged from 0.83 to 1.83 mm. Biplane, on-line, digital coronary angiograms and cineangiograms were recorded during standard selective coronary arteriography in the closed-chest preparation. The on-line digital images were analyzed in nonsubtracted and subtracted modes. Cineangiograms were digitized to allow coronary quantitation by the same computer program. There was an excellent correlation between known and measured minimal diameter stenoses (r = .87 to .98, SEE = 0.09 to 0.24 mm). Interobserver and intraobserver variability analysis showed high reproducibility (r = .90 to .97, SEE = 0.12 to 0.23 mm). The best results in both analyses were achieved by nonsubtracted digital imaging and the worst by cineradiography. Measures of percent diameter stenosis, percent area stenosis (geometric and videometric), and absolute minimal cross-sectional area (geometric and videometric) were all significantly correlated with independent measures of actual coronary flow reserve. This study provides direct anatomic and physiologic validation in vivo of a new and rapid coronary quantitation method suitable for analysis of both digital angiograms and cineangiograms.

Reduction of reperfusion injury in the canine preparation by intracoronary adenosine: importance of the endothelium and the no-reflow phenomenon.

Abstract: We hypothesized that the endogenous coronary vasodilator adenosine may reduce infarct size by progressively increasing reflow in a preparation of coronary occlusion-reperfusion. After 90 min of proximal left anterior descending artery occlusion, 20 dogs were randomized to blood reperfusion with (n = 10) or without (n = 10) adenosine into the proximal left anterior descending vessel at 3.75 mg/min for 60 min after reperfusion. Regional myocardial blood flow was determined serially with microspheres and regional ventricular function was assessed by a computerized radial shortening method. At 24 hr, the area at risk was defined in vivo with monastral blue dye and area of necrosis was determined after incubation of left ventricular slices in triphenyltetrazolium chloride. Hemodynamic variables were similar in the two groups during the experimental protocol. Infarct size was significantly reduced in treated animals, both when expressed as a percentage of the area at risk (9.9 +/- 2.8% vs 40.9 +/- 6.6%, p less than .001) and as a percentage of the left ventricle (4.6 +/- 1.3% vs 18.0 +/- 3.4%, p = .002). This was associated with significant improvement in radial shortening in the ischemic zone 24 hr after reperfusion (10.1 +/- 2.5 vs -2.8 +/- 2.2%, p less than .01). Regional myocardial blood flow was significantly increased in endocardial and epicardial regions from the lateral ischemic zone 1 hr after reperfusion in adenosine-treated animals. Light microscopy demonstrated decreased neutrophil infiltration in the ischemic zone and electron microscopy showed relative preservation of endothelial structure in the subendocardium with reduced neutrophil and red cell stagnation of capillaries in the treated group. These findings suggest that intracoronary administration of adenosine after reperfusion significantly reduces infarct size and improves regional ventricular function in the ischemic zone in the canine preparation.

The effect of intravenous thrombolytic therapy on left ventricular function: a report on tissue-type plasminogen activator and streptokinase from the Thrombolysis in Myocardial Infarction (TIMI Phase I) trial.

Abstract: In Phase I of the NHLBI trial of Thrombolysis in Myocardial Infarction (TIMI), 290 patients admitted within 7 hr after onset of acute infarction were randomly assigned to intravenous treatment with either streptokinase (SK) or recombinant tissue-type plasminogen activator (rt-PA). Left ventricular function was measured from contrast ventriculograms in 145 patients with both pretreatment and predischarge studies analyzable. Regional wall motion in the infarct site was measured by the centerline method and expressed in units of standard deviations (SDs) from the mean motion in 52 normal subjects. Patients treated with rt-PA (n = 77) achieved a significantly higher reperfusion rate after 90 min of treatment. Perfusion of the infarct-related artery improved from visual grade 0 or 1 (total occlusion or penetration without perfusion) to grade 2 or 3 (partial or full reperfusion) in 62% receiving rt-PA vs 31% receiving SK (n = 68) (p less than .001). However, the ejection fraction did not change significantly from before treatment to before discharge in either treatment group (+0.7 +/- 6.7% vs +1.0 +/- 8.3%, respectively). A small but significant increase in regional wall motion was observed in each of the two groups (+0.4 +/- 0.8 vs +0.3 +/- 0.8 SD/chord, respectively; each p less than .001 compared with baseline). This was countered by declines in the hyperkinesis of the noninfarct region (-0.3 +/- 1.0 SD/chord [p = .01] compared with baseline and -0.2 +/- 1.0 SD/chord [p = .23], respectively). Analysis of the combined groups revealed that the ejection fraction increased only in patients who achieved reperfusion by 90 min after onset of therapy or who had subtotal occlusions initially. There was greater recovery of left ventricular function in patients who achieved reperfusion earlier vs later than 4 hr after symptom onset and in patients with vs without some collateral circulation to the infarct-related artery.

The spectrum of left ventricular hypertrophy in a general population sample: the Framingham Study.

Abstract: To assess the prevalence, characteristics, and correlates of echocardiographically determined left ventricular hypertrophy (echo LVH) in a free-living population, 510 men and 855 women from the original Framingham cohort (age 59 to 90 years) were studied by M-mode echocardiography. Offspring and offspring spouses (1718 men and 1892 women; age 17 to 75 years) were similarly studied. The severity of echo LVH, as reflected by left ventricular mass indexed to body surface area, ranged from 101 g/m2 (women) and 132 g/m2 (men) to more than 400 g/m2. The prevalence of electrocardiographically assessed LVH increased proportionately with increased echocardiographic left ventricular mass. Women with echocardiographic left ventricular mass indexes exceeding 200 g/m2 were three to four times more likely to have electrocardiographic LVH than men with similar elevations of echocardiographic left ventricular mass index. The prevalence of echo LVH ranged from 6.6% in the younger (offspring study) women to 33% in the older (original cohort) women (8.6% and 23.7%, respectively, for men) and included a spectrum of forms--eccentric-dilated, eccentric-nondilated, concentric, and disproportionate septal thickness--which varied in prevalence in the various age-sex groups. Each of these forms of echo LVH was associated with higher systolic blood pressures at the time of echocardiographic examination and over the previous 30 years when compared with blood pressures of Framingham subjects without echo LVH.

Biochemical evidence of a chronic abnormality in platelet and vascular function in healthy individuals who smoke cigarettes.

Abstract: Cigarette smoking is associated with increased mortality from cardiovascular disease that declines after cessation. This study extends the evidence regarding the effects of chronic smoking on platelets and the vessel wall in vivo. Excretion of a major urinary thromboxane metabolite, 2,3-dinor-thromboxane B2, is significantly (p less than .01) elevated in apparently healthy chronic smokers (20 cigarettes daily) compared with that in nonsmoking control subjects. This difference in excretion of 2,3-dinor-thromboxane B2 was abolished by the administration of 20 mg aspirin twice daily, a dose shown to selectively inhibit platelet cyclooxygenase. After aspirin, the return of the excretion of 2,3-dinor-thromboxane B2 to pretreatment levels paralleled the recovery of platelet cyclooxygenase. These findings indicate that excessive thromboxane A2 generation in chronic smokers predominantly derives from platelets. The urinary excretion of the prostacyclin metabolite 2,3-dinor-6-keto-prostaglandin F1 alpha also is increased during chronic cigarette smoking, as is the case with other diseases associated with accelerated interaction of platelets with the vessel wall. We have found evidence of platelet and vascular dysfunction in vivo in chronic cigarette smokers before the manifestation of overt cardiovascular disease. The results would also be consistent with the hypothesis that in chronic smokers, the platelet defect is largely reflective of smoking-induced vascular injury.

Balloon-expandable intracoronary stents in the adult dog.

Abstract: We studied the acute and chronic biological reaction to balloon-expandable intracoronary stents in the adult dog. Twenty stainless steel stents were placed, by standard angioplasty techniques, into the left anterior descending, left main, or circumflex coronary arteries of 20 dogs. Angiography was performed at 1, 3, 6, and 12 months and animals were killed in groups of three at 1, 3, 8, and 32 weeks, for gross, light, and electronmicroscopic analysis. All dogs survived, all stents were patent, and there was no evidence of myocardial infarction, spasm, rupture, or aneurysm formation during follow-up (longest 18 months; average, 12 months). The stent was initially covered by a thin layer of thrombus that was replaced later by neointimal muscular proliferation that reached its maximal thickness by 8 weeks (p less than .01). This neointima gradually thinned as it became more sclerotic and less cellular. The stents were covered completely by immature endothelium by 1 week without loss of side branches. We conclude that balloon-expandable intraluminal stents can be safely placed percutaneously into normal canine coronary arteries. Because of rapid endothelialization high patency rates can be expected, thus offering promise for clinical applications in man.

High-dose calcium channel-blocking therapy for primary pulmonary hypertension: evidence for long-term reduction in pulmonary arterial pressure and regression of right ventricular hypertrophy

Abstract: In an attempt to produce substantial reductions in pulmonary arterial pressure and pulmonary vascular resistance in patients with primary pulmonary hypertension, a new treatment strategy using high doses of calcium channel-blocking drugs was developed. Thirteen patients were given an initial test dose of 60 mg diltiazem or 20 mg nifedipine followed by consecutive hourly doses until a 50% fall in pulmonary vascular resistance and 33% fall in pulmonary arterial pressure was achieved or untoward side effects developed. The initial drug challenges failed to produce significant reductions in mean pulmonary arterial pressure or pulmonary vascular resistance. In eight of 13 patients, continued hourly doses produced a reduction in mean pulmonary arterial pressure of 48% (61 to 35 mm Hg, p less than .01) and a reduction in pulmonary vascular resistance of 60% (15 to 6 units, p less than .01). These patients were discharged on high-dose (up to 720 mg/day diltiazem or 240 mg/day nifedipine) calcium channel-blocking drugs as long-term therapy. Five patients have returned for restudy after 1 year. In four of five the reductions in pulmonary arterial pressure and pulmonary vascular resistance were sustained and were associated with regression of right ventricular hypertrophy as assessed by electrocardiography and echocardiography. One patient who reduced her dose to a conventional level had a return of her pulmonary arterial pressure and pulmonary vascular resistance toward previous levels. We conclude that substantial reductions in pulmonary arterial pressure and pulmonary vascular resistance that are associated with regression of right ventricular hypertrophy are possible in some patients with primary pulmonary hypertension by use of calcium channel-blocking drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Monophasic action potential mapping in human subjects with normal electrocardiograms: direct evidence for the genesis of the T wave.

Abstract: T wave concordance in the normal human electrocardiogram (ECG) generally is explained by assuming opposite directions of ventricular depolarization and repolarization; however, direct experimental evidence for this hypothesis is lacking. We used a contact electrode catheter to record monophasic action potentials (MAPs) from 54 left ventricular endocardial sites during cardiac catheterization (seven patients) and a new contact electrode probe to record MAPs from 23 epicardial sites during cardiac surgery (three patients). All patients had normal left ventricular function and ECGs with concordant T waves. MAP recordings during constant sinus rhythm or right atrial pacing were analyzed for activation time (AT) = earliest QRS deflection to MAP upstroke, action potential duration (APD) = MAP upstroke to 90% repolarization, and repolarization time (RT) = AT plus APD. AT and APD varied by 32 and 64 msec, respectively, over the left ventricular endocardium and by 55 and 73 msec, respectively, over the left ventricular epicardium. On a regional basis, the diaphragmatic and apicoseptal endocardium had the shortest AT and the longest APD, and the anteroapical and posterolateral endocardium had the longest AT and the shortest APD (p less than .05 to less than .0001). RT was less heterogeneous than APD, and no significant transventricular gradients of RT were found. In percent of the simultaneously recorded QT interval, epicardial RT ranged from 70.8 to 87.4 (mean 80.7 +/- 3.9) and endocardial RT ranged from 80 to 97.8 (mean 87.1 +/- 4.4) (p less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Skeletal muscle metabolism in patients with congestive heart failure: relation to clinical severity and blood flow.

Abstract: We and others have previously demonstrated excessive phosphocreatine (PCr) depletion and acidosis in skeletal muscle during exercise in patients with congestive heart failure (CHF). In the present study, we performed serial measurements of PCr and pH during gradually incremental flexor digitorum superficialis exercise in 22 patients with CHF and 11 age-matched controls to determine: (1) whether abnormalities were present at the same relative workloads (a comparison that would at least partially compensate for differences in muscle mass), (2) the temporable course of the metabolic changes, (3) the relationship of the metabolic findings to clinical variables, and (4) the relationship of the metabolic abnormalities to forearm blood flow. The patients with CHF had significantly lower [PCr] and pH at all submaximal levels of exercise, and these abnormalities were apparent from the onset of low-level exercise. There was considerable heterogeneity among the patients with CHF with respect to the metabolic findings, with 14 of 22 exhibiting either PCr or pH values more than 2 SDs below normal. Patients whose capacity was more limited during the protocol had lower [PCr], and especially pH, at low loads than did other patients with CHF or the control subjects. The more symptomatic patients and those with more limited bicycle exercise tolerance also had lower pH values. In contrast, there were no significant differences in forearm blood flow between the patients and controls and no relationship between forearm blood and either clinical variables or the metabolic findings. These results indicate that skeletal muscle metabolic abnormalities are present in many patients with CHF and that they are not primarily due to either muscle atrophy or impaired blood flow. These changes may explain in part the marked heterogeneity of symptom status and exercise capacity of patients with similar degrees of cardiac dysfunction.

Coronary hemodynamics and myocardial metabolism of lactate, free fatty acids, glucose, and ketones in patients with septic shock.

Abstract: To investigate disturbances in the coronary circulation and myocardial metabolism during septic shock, we examined coronary sinus blood flow and myocardial substrate extraction in 40 patients with septic shock and 13 control patients. Patients with coronary artery disease were excluded from this study. The global hemodynamic pattern of the septic patients was characterized by a lower stroke volume, despite an elevated cardiac index. Coronary sinus blood flow was high (187 +/- 47 vs 130 +/- 21 ml/min in the control group, p less than .001) due to marked coronary vasodilation, especially in the subgroup of nonsurvivors. In contrast to the control group, myocardial lactate uptake was elevated, while that of free fatty acids, glucose, and ketone bodies was diminished in patients with septic shock. These findings were especially prominent in the nonsurvivors. Expressed as oxygen equivalents, the contribution of free fatty acids as an energy source of the myocardium was markedly diminished in septic patients (12% vs 54% in the control group, p less than .005), while that of lactate was increased (36% vs 12%, p less than .01). The observed shift in myocardial substrate extraction was associated with a discrepancy between measured myocardial oxygen consumption and that calculated chemically from commonly available exogenous substrates: 41% of myocardial oxygen consumption was not explained by the utilization of commonly available substrates extracted from coronary circulation in all patients with septic shock.(ABSTRACT TRUNCATED AT 250 WORDS)

Prediction of the physiologic significance of coronary arterial lesions by quantitative lesion geometry in patients with limited coronary artery disease.

Abstract: Studies in animals with normal coronary arteries have shown that coronary flow reserve can be predicted by angiographic measurements of arterial stenosis. Studies in man, however, suggest that even quantitative analysis of coronary angiograms cannot predict the physiologic significance of individual coronary lesions. These studies, however, were carried out in patients with either widespread, diffuse coronary artery disease or by measurement techniques that tend to underestimate maximal coronary flow reserve. To determine the relationship between coronary arterial stenosis and coronary flow reserve (CFR) in patients with discrete limited coronary atherosclerosis, we studied 50 patients with a single discrete coronary stenosis in only one or two vessels. The minimum coronary arterial cross-sectional area (mCSA), percent area stenosis (%AS), and percent diameter stenosis in the left and right anterior oblique projections were determined by the Brown/Dodge method of quantitative coronary angiography. A No. 3F coronary Doppler catheter was placed immediately proximal to the lesion. Measurements of CFR were obtained by intracoronary administration of papaverine in doses sufficient to provide maximal arteriolar vasodilation. In 25 patients, a translesional pressure gradient was obtained with an angioplasty catheter. CFR measured in patients with coronary artery disease was compared with that in 13 patients with normal coronary vessels. In normal patients, CFR averaged 5.0 +/- 0.6 (peak/resting velocity ratio; mean +/- SEM, range 3.7 to 8.2). In patients with limited coronary artery disease, CFR was closely correlated with %AS (r = .85), mCSA (r = .79), and the translesional pressure gradient (r = .83). Additionally, the most severe percent diameter stenosis in either the left or right anterior oblique view was also highly correlated with CFR (r = .82). Importantly, all arteries with lesions producing less than 70% area stenosis and less than 50% diameter stenosis, or with greater than 2.5 mm2 mCSA had CFR of over 3.5. These results suggest that, in contrast to the poor correlation of percent area and percent diameter stenosis to CFR measured in patients with multivessel coronary artery disease, CFR measured at angiography in patients with discrete, limited coronary artery disease correlates closely with luminal stenosis determined precisely with quantitative coronary angiography. Differences in the extent of diffuse arterial narrowing may account for these discrepancies.

Clinical application of atrial natriuretic polypeptide in patients with congestive heart failure: beneficial effects on left ventricular function.

Abstract: Synthetic alpha-human atrial natriuretic polypeptide was infused in patients with congestive heart failure (CHF) (New York Heart Association class III or IV) and in those without CHF. The infusion of atrial natriuretic polypeptide (ANP) at a rate of 0.1 microgram/kg/min significantly decreased pulmonary capillary wedge pressure and increased stroke volume index in all of the patients with CHF, whereas it decreased pulmonary capillary wedge pressure but caused no significant change in stroke volume index in the patients without CHF. Concomitant significant reductions in total systemic resistance were observed in both groups of patients. The ANP infusion significantly increased the urine volume, the excretion of sodium, and endogenous creatinine clearance in the patients without CHF. In the patients with CHF, it also showed a tendency to increase all these variables, but the urine volume did not correlate with the reduction in pulmonary capillary wedge pressure. The ANP infusion also decreased plasma aldosterone concentrations in these patients, although no significant difference was observed in the decrement of the plasma aldosterone concentration in the patients with and those without CHF. These findings indicate that the ANP infusion improves left ventricular function in patients with CHF, and suggest that this improvement results mainly from the vasodilating activity of ANP.

The relative importance of selected risk factors for various manifestations of cardiovascular disease among men and women from 35 to 64 years old: 30 years of follow-up in the Framingham Study

Abstract: Substantial differences were noted in the risk profiles for various manifestations of cardiovascular disease (CVD) that occurred before the age of 65 during the first 30 years of follow-up of the 5070 subjects of the original Framingham cohort. Hypertension contributed most consistently to short-term risk of all manifestations of CVD. Differences were noted between the sexes and age groups in both the univariate and multivariate analyses. These patterns have biological, clinical, and statistical significance, particularly as they relate to the need for future studies to distinguish better between those factors that precipitate cardiovascular events and those that relate to the pathogenesis of the underlying atherosclerosis.

Percutaneous balloon valvotomy for patients with severe mitral stenosis.

Abstract: Thirty-five patients with severe mitral stenosis underwent percutaneous mitral valvotomy (PMV). There were 29 female and six male patients (mean age 49 +/- 3 years, range 13 to 87). After transseptal left heart catheterization, PMV was performed with either a single- (20 patients) or double- (14 patients) balloon dilating catheter. Hemodynamic and left ventriculographic findings were evaluated before and after PMV. There was one death. Mitral regurgitation developed or increased in severity in 15 patients (43%). One patient developed complete heart block requiring a permanent pacemaker. PMV resulted in a significant decrease in mitral gradient from 18 +/- 1 to 7 +/- 1 mm Hg (p less than .0001) and a significant increase in both cardiac output from 3.9 +/- 0.2 to 4.6 +/- 0.2 liters/min (p less than .001) and in mitral valve area from 0.8 +/- 0.1 to 1.7 +/- 0.2 cm2 (p less than .0001) Effective balloon dilating diameter per square meter of body surface area correlated significantly with the decrease in mitral gradient but did not correlate with the degree of mitral regurgitation. There was no correlation of age, prior mitral commissurotomy or mitral calcification with hemodynamic results. PMV is an effective nonsurgical procedure for patients with mitral stenosis, including those with pliable valves, those with previous commissurotomy, and even those with mitral calcification.

Isolated atrial septal defect with pulmonary vascular obstructive disease--long-term follow-up and prediction of outcome after surgical correction.

Abstract: We examined the cases of 702 patients found to have isolated atrial septal defect of the secundum or sinus venosus type at catheterization from 1953 to 1978. Forty patients (6%), 34 women and six men, had pulmonary vascular obstructive disease, with a total pulmonary resistance greater than 7 U/m2; of these patients 26 (mean age 47 years) underwent surgical closure and 14 (mean age 44 years) received medical treatment. All patients were followed for at least 4 years, with a median follow-up of 12 years. At the most recent follow-up, 17 of the 40 patients were dead. Of the 22 surgically treated patients with total pulmonary resistance less than 15 U/m2, 19 were alive with significant regression of symptoms. All four surgically treated patients with total pulmonary resistance greater than or equal to 15 U/m2 were dead. Of the five medically treated patients with total pulmonary resistance less than 15 U/m2, four had died, and one was alive with significant progression of symptoms. Of the nine medically trea...

Aspirin and dipyridamole in the prevention of acute coronary thrombosis complicating coronary angioplasty.

Abstract: To test the hypothesis that pretreatment with adequate antiplatelet therapy reduces the likelihood of acute coronary thrombosis during routine percutaneous transluminal coronary angioplasty (PTCA), we reviewed, blinded to treatment group, the films and records of 300 consecutive initially successful PTCAs. Films before PTCA, immediately after, and at least 30 min after the last balloon inflation were assessed for the presence of any thrombus at the PTCA site. We excluded 37 patients who received streptokinase before PTCA or who had 100% occlusion or thrombus on pre-PTCA films. New thrombi were classified as clinically significant (defined as causing 100% occlusion or requiring emergency surgery or streptokinase therapy) or as not significant (not causing an acute problem or requiring intervention). Patients were classified into three groups, based on the type and extent of antiplatelet therapy received. Group 1 (no aspirin, n = 121) consisted of patients who did not receive aspirin either before admission or in hospital before PTCA (with or without dipyridamole). Group 2 (standard treatment, n = 110) received aspirin with or without dipyridamole but did not receive both drugs before admission and in hospital before PTCA. Group 3 (maximal treatment, n = 32) received both aspirin and dipyridamole before admission and in hospital before PTCA. New thrombi were detected at 39 (14.8%) PTCA sites, of which 15 (5.7% of all PTCA sites) were considered clinically significant. Group 1 had the highest incidence of both thrombus (21.5%) and clinically significant thrombus (10.7%). A reduction was seen in group 2 in thrombus (11.8%; p = .07) and in clinically significant thrombus (1.8%; p = .005). Group 3 had no thrombus (p = .001) and no clinically significant thrombus (p = .04). In addition to inadequate pretreatment with antiplatelet therapy, univariate analyses demonstrated several other risk factors for thrombus: higher percent diameter stenosis before PTCA (p less than .008), higher platelet count (p = .013), and current smoking (p = .03). Only higher platelet count (p less than .001) and inadequate pretreatment (p = .001) were associated with clinically significant thrombus. Stepwise logistic regression analysis demonstrated that for thrombus, the lack of effective antiplatelet therapy was the most discriminatory variable, followed by current smoking, higher percent diameter stenosis, and dissection. For clinically significant thrombus, once the lack of pretreatment with effective antiplatelet therapy was considered, no other factors added significant discriminatory information.(ABSTRACT TRUNCATED AT 400 WORDS)

Measurements of coronary flow reserve: defining pathophysiology versus making decisions about patient care.

Abstract: THE POTENTIAL ATTRACTIVENESS of measurement ofcoronary flow reserve in an area ofmyocardium supplied by a stenosed coronary artery has long been recognized. As options for quantifying flow reserve in man have improved, there has been increasing interest in the use of flow reserve measurements to make individual patient care decisions as well as to define pathophysiology in patient groups. The requirements for effective use in individual patients are in many ways more stringent than in patient groups. Factors that must be considered on an individual rather than group basis include effects of variables potentially affecting flow reserve independently of degree of stenosis, theoretical and practical limitations of specific measurement techniques, and confidence limits for procedurally satisfactory measurements. Factors underlying interest in measurements of flow reserve in man Limitations of arteriographic estimates of stenosis severity. Despite the acknowledged pivotal role of coronary arteriography in management decisions in patients with coronary heart disease, the functional significance of an arteriographic lesion often cannot be settled from the arteriogram alone. This point has been emphasized by a number of experimental studies of stenosis behavior, particularly those of Gould.1 It is generally agreed that limitations of arteriographic measurements are most troublesome for stenoses ofmoderate-to-severe degree, i.e., 50% to 90% diameter narrowing. Because of the

The relationship of mitral annular shape to the diagnosis of mitral valve prolapse.

Abstract: The geometric or anatomic diagnosis of mitral valve prolapse, as opposed to the pathologic diagnosis of myxomatous valve disease, is based on the relationship of the mitral leaflets to the surrounding anulus. Current echocardiographic criteria for this diagnosis include leaflet displacement above the annular hinge points in any two-dimensional view; implicit in this equivalent use of intersecting views is the assumption that the mitral anulus is a euclidean plane. Prolapse by these criteria is found in a surprisingly large proportion of the general population. In most of these individuals, however, prolapse is present in the apical four-chamber view and absent in roughly orthogonal long-axis views of the left ventricle. This frequently observed discrepancy between leaflet-annular relationships in intersecting views suggests an underlying geometric property of the mitral apparatus that would produce the appearance of prolapse in one view without actual leaflet distortion. To address this possibility, a model of the mitral valve and anulus was constructed. When the model anulus was given a nonplanar, saddle-shaped configuration, the clinical observations were reproduced: the leaflets appeared to lie above the low points of the anulus in one plane, and below its high points in a perpendicular plane. Therefore, the appearance of mitral valve prolapse can occur without actual leaflet displacement above the most superior points of the mitral anulus if the anulus is nonplanar. To determine whether this pattern is reflected in the human mitral anulus, two-dimensional echocardiographic views of the mitral apparatus were obtained by rotation about the cardiac apex in 20 patients without evident annular or rheumatic valvular disease. In all cases the mitral anulus, as reconstructed from these views, had a nonplanar systolic configuration, with high points located anteriorly and posteriorly. This is consistent with the findings of other groups in animals, and would favor the appearance of prolapse in the four-chamber view and its absence in long-axis views that are oriented anteroposteriorly. This model can therefore explain the frequently observed discrepancy between leaflet-annular relationships in roughly orthogonal views. It challenges the assumption that the mitral anulus is planar as well as the diagnosis of prolapse in many otherwise normal individuals based on that assumption.