Plasma lipid concentrations and subsequent coronary occlusion after a first myocardial infarction. The POSCH Group.

This study correlated plasma lipid values with angiographic evidence of progression to complete coronary occlusion. Baseline triglycerides (TGs), total cholesterol (Chol), high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, very low density lipoprotein (VLDL) cholesterol, and HDL/LDL and HDL/Chol ratios were compared with coronary angiograms taken at baseline, 3 and 5 years in a prospective angiographic study. Results were from part of the multicenter trial of plasma lipid reduction in patients after a single myocardial infarction (POSCH). Comparison of patient's baseline lipids in the absence or presence of a new total coronary occlusion at 3 years showed a significant difference (p = 0.01) in TGs of 197 +/- 147 versus 250 +/- 162 mg/dl (p = 0.02) and VLDL of 30 +/- 23 (n = 284) versus 40 +/- 30 (n = 49) mg/dl. Stratification by the mean HDL/Chol ratio (16%) demonstrated that baseline TG levels were significantly increased in patients with a new coronary occlusion by 3 years despite a higher HDL/Chol ratio. When measured at the 3-year visit, plasma TG (176 +/- 91 versus 212 +/- 146 mg/dl; p = 0.02) and VLDL (28 +/- 18 versus 35 +/- 29 mg/dl; p = 0.04) were significantly elevated in the presence of a new 3-year coronary occlusion. Stratification by the mean HDL/Chol ratio (16%) demonstrated that 3-year TG levels increased significantly in patients with a new 3-year coronary occlusion despite a higher HDL/Chol ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in sequential coronary arteriograms and subsequent coronary events. Surgical Control of the Hyperlipidemias (POSCH) Group.

OBJECTIVE: Assessment of the relationship between changes in sequential coronary arteriograms and subsequent clinical coronary events. DESIGN: The Program on the Surgical Control of the Hyperlipidemias, a randomized secondary atherosclerosis intervention trial, obtained coronary arteriograms at baseline, 3, 5, and 7 or 10 years of follow-up. Assessments of changes between pairs of coronary arteriograms were made by two-member panels blinded to the patients' assigned treatment and to the temporal sequence of the films. The relationship of changes between the baseline and the 3-year follow-up arteriograms and subsequent clinical coronary events was examined. SETTING: Three university hospitals and one private primary care facility. PATIENTS: A total of 838 patients, with 417 patients randomized to the control group and 421 to the intervention group. Of all patients, 695 had baseline and 3-year arteriograms. INTERVENTION: The control group received American Heart Association Phase II diet instruction and the intervention group received identical dietary instruction plus a partial ileal bypass operation. MAIN OUTCOME MEASURE: The use of arteriographic changes as a predictor of subsequent clinical coronary events. RESULTS: Changes between the baseline and the 3-year coronary arteriographic overall disease assessment were significantly associated with subsequent overall and atherosclerotic coronary heart disease mortality (P less than .01). For the combined end point of atherosclerotic coronary heart disease mortality or confirmed nonfatal myocardial infarction, a significant relationship between the overall disease assessment and subsequent clinical events was found in the control group (P less than .0001) and in the surgery group (P = .04). For this combined end point, however, the control and the surgery groups were different with respect to clinical coronary events after 3 years, stratified by the baseline to 3-year overall disease assessment (P less than .001, unadjusted; P = .06, adjusted for 3-year clinical covariates). CONCLUSIONS: Coronary arteriographic changes can be used in atherosclerosis intervention trials as a limited surrogate end point for certain clinical coronary events. This relationship is statistically compelling for overall mortality and atherosclerotic coronary heart disease mortality. For an individual patient, changes in the severity of coronary atherosclerosis seen on sequential coronary arteriograms can serve as prognostic indicators for subsequent overall or atherosclerotic coronary heart disease mortality.

Pharmacokinetic characterization of the postdistribution phase of prohormone atrial natriuretic peptides amino acids 1-98, 31-67, and atrial natriuretic factor during and after rapid right ventricular pacing in dogs.

Release rate constants and disappearance rate constants were determined for three atrial natriuretic peptides consisting of amino acids 1-98 (i.e., proANF 1-98), the midportion of the ANF prohormone consisting of amino acids 31-67 (i.e., proANF 31-67) and amino acids 99-126 (i.e., ANF) after right ventricular pacing at 100, 125, 150, and 180 bpm in six male mongrel dogs. Right atrial and femoral vein blood was obtained at baseline, and at 5, 12, 19, 26, 56, 86, 116, 146, and 206 minutes after right ventricular pacing. Resulting plasma concentration-time data derived parameters were compared. The disappearance rate constants for atrial and femoral venous proANF 1-98 were 0.0144 +/- 0.0087 (X +/- SD) and 0.0175 +/- 0.0075 min-1, respectively (t = 0.6158) and release rate constants were 0.1569 +/- 0.1504 and 0.0670 +/- 0.0393 min-1, respectively (t = 1.8269; P greater than .05). The proANF 31-67 disappearance rate constants were 0.0139 +/- 0.0082 and 0.0148 +/- 0.0132 min-1, respectively (t = 0.1192) and release rate constants were 0.0957 +/- 0.0414 and 0.1984 +/- 0.1762 min-1, respectively (t = 1.4812). The ANF elimination phase disappearance rate constants were 0.0663 +/- 0.0273 and 0.1116 +/- 0.0539 min-1 (t = 2.0923, P greater than .05), respectively, and the release rate constants were 0.1335 +/- 0.0532 and 0.1638 +/- 0.0520 min-1 (t = 0.7878, P greater than .05), respectively. These data indicate that proANF 1-98 and proANF 31-67 circulating beta post-distribution half-lives are approximately 45 minutes whereas beta half-life of ANF is 10 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute and sustained release of the atrial natriuretic factor prohormone N-terminus with acute myocardial infarction.

This investigation was designed to determine if acute ischemic cardiac injury causes the release of the 98 amino acid (aa) N-terminus of the 126 aa atrial natriuretic factor prohormone (pro ANF). Seventeen patients with acute myocardial infarction, but without clinical evidence of congestive heart failure, had their circulating concentrations of the whole N-terminus (ie, pro ANF 1-98), the midportion of the N-terminus of the ANF prohormone (consisting of aa 31-67; pro ANF 31-67) and creatine phosphokinase (CPK) monitored daily for 14 days. All seventeen patients had elevated plasma pro ANF 1-98 and pro ANF 31-67 concentrations at the time of presentation. Maximal increase on day three post-infarction correlated with the size of infarction estimated by the maximal CPK (r = 0.675; p less than 0.05) but did not correlate with the amount of left ventricular dysfunction. Another three patients with acute myocardial infarction were treated with tissue plasminogen activator (tPA). The measured pro ANF 1-98 and pro ANF 31-67 levels in these patients were within our normal range and significantly lower (p less than 0.001) than seen in patients with acute myocardial infarction not given thrombolytic therapy. Six patients with unstable angina, likewise, had normal circulating pro ANFs 1-98 and 31-67 concentrations during prolonged episodes of chest pain. These data suggest that myocardial necrosis but not ischemia triggers the release of the entire 126 aa prohormone.

Angiographic progression to total coronary occlusion in hyperlipidemic patients after acute myocardial infarction. POSCH Group.

The progression of coronary artery stenosis to total occlusion was assessed in 413 hyperlipidemic patients with a previous myocardial infarction. Coronary angiograms were recorded at baseline, 3 (n = 312), and 5 years (n = 248) after initial study and analyzed by 2 independent readers. There were 177 (43%) patients with 1-, 130 (31%) with 2-, and 61 (15%) with 3-vessel disease (greater than or equal to 50% diameter narrowing), whereas 45 (11%) did not have significant disease within a major coronary vessel at baseline. A new finding of total occlusion occurred in 4% (30 of 748) and 7% (40 of 605) of major coronary artery segments at 3 and 5 years, respectively. The risk of progression to total occlusion was higher if the initial stenosis was greater than 60% compared to lesions less than or equal to 60% both at 3 years (19 of 143 = 13% vs 11 of 605 = 2%; p less than 0.001) and 5 years (27 of 91 = 30% vs 13 of 514 = 3%; p less than 0.001). The frequency of occlusion was highest for the right coronary artery by 5 years (18 of 167 = 11% for right vs 8 of 225 = 4% for circumflex vs 14 of 213 = 7% for left anterior descending coronary arteries; p less than 0.02). Clinical and laboratory data revealed that myocardial infarction was associated with a new total occlusion in 23% of patients (7 of 30) at 3 years and in 64% (25 of 39) at 5 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma prohormone atrial natriuretic peptides 1-98 and 31-67 increase with supraventricular and ventricular arrhythmias.

Recently two peptides consisting of amino acids (AA) 1-30 and 31-67 of the N-terminus of the 126 AA prohormone of atrial natriuretic factor (pro ANF) as well as atrial natriuretic factor (ANF, AA 99-126; C-terminus) were found to have vasodilatory and natriuretic properties. These peptides as well as ANF circulate in man as part of the N-terminus of the prohormone. To determine if the polyuria, associated with both ventricular and supraventricular arrhythmias, is associated with increased circulating concentrations of the N-terminus and C-terminus of the ANF prohormone, 20 individuals with spontaneous arrhythmias, including ten persons with atrial fibrillation, six with paroxysmal supraventricular tachycardia, and four with ventricular tachycardia, were evaluated before and after conversion to sinus rhythm. In all 20 patients, the circulating concentrations of the whole N-terminus (ie, AA 1-98), the midportion of the N-terminus (pro ANF 31-67) that circulates as a distinct 3900 molecular weight peptide after being proteolytically cleaved from the N-terminus, and the C-terminus were significantly higher (p less than 0.001) than their concentration in 54 persons with sinus rhythm. With conversion to sinus rhythm, the plasma C-terminus concentration of these 20 arrhythmia patients decreased to the level of persons with sinus rhythm within 30 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute and sustained release of atrial natriuretic factor with acute myocardial infarction.

The present investigation was designed to determine if acute ischemic cardiac injury causes the release of atrial natriuretic factor (ANF). Seventeen patients with acute myocardial infarction but without clinical evidence of congestive heart failure had their circulating concentration of ANF and creatine phosphokinase monitored daily for 14 days. All 17 patients had an elevated plasma ANF concentration at time of presentation. Maximal increase in ANF was on day 2 and 3 post-infarction. This maximal increase correlated with the size of infarction estimated by the maximal creatine phosphokinase concentration (r = 0.475; p less than 0.05), but did not correlate with the amount of left ventricular dysfunction. ANF began to decrease by day 4 post-infarction and was normal at 10 days post-infarction in 14 of the 17 (82%) patients. At 12 days post-infarction, all 17 patients had normal ANF levels. Another three patients with acute myocardial infarction were treated with tissue plasminogen activator (tPA). The measured ANF levels in these patients were within our normal range and were significantly lower (p less than 0.001) than those seen in patients with acute myocardial infarction not given thrombolytic therapy. Six patients with unstable angina likewise had normal circulating ANF concentrations during prolonged episodes of chest pain. These levels were also significantly lower (p less than 0.001) than the 17 patients with acute infarcts not given tPA. The distinct pattern of release of ANF may be useful as an adjunct to serum cardiac enzymes in determining if a myocardial infarction has occurred.

Prohormone atrial natriuretic peptides 1-30, 31-67, and 99-126 increase in proportion to right ventricular pacing rate.

To determine whether heart rate contributes to release of three new peptide hormones synthesized in the heart, right ventricular pacing at rates of 100, 125, 150, and 180 bpm was performed in six dogs with measurement of the plasma concentration of these peptides at each pacing rate while right atrial and systemic blood pressures were simultaneously monitored. These three peptides of the 126-amino-acid prohormone of atrial natriuretic factor (ANF), consisting of amino acids 1-30 (pro ANF 1-30), 31-67 (pro ANF 31-67), and 99-126 (ANF), increased incrementally at paced heart rates of 125, 150, and 180 bpm (r = 0.8, p less than 0.001). Right atrial pressure decreased with increasing heart rate but systemic blood pressure did not decrease until the heart rate was 180 bpm, at which time these peptides had obtained their maximal circulating concentrations. After pacing, mean right atrial pressure and levels of ANF returned to prepacing values within 30 minutes. Mean arterial blood pressure, on the other hand, increased throughout the 120-minute period after pacing. At 2 hours after pacing, levels of pro ANFs 1-30 and 31-67 were elevated compared with prepacing values. These data demonstrate that, at heart rates of 125 bpm and above, pro ANF 1-30, pro ANF 31-67, and ANF (99-126) are simultaneously and incrementally released in direct proportion to heart rate. The sustained elevation in pro ANFs 1-30 and 31-67 seen 2 hours after pacing suggests that they may contribute to the prolonged diuresis seen after cardiac pacing or tachycardia.

Residual myocardial jeopardy in patients with Q-wave and non-Q-wave infarctions.

The correlation between the presence of areas of jeopardized myocardium and the electrocardiographic patterns of anterior and inferior Q-wave and non-Q-wave infarctions was studied in 486 patients who had had stable symptoms for at least six months after a single myocardial infarction. Myocardial jeopardy was identified on a ventriculogram in the right anterior oblique position if normal or hypokinetic wall motion was seen in all segments distal to a lesion that caused stenosis of greater than 50% and less than 100% in the proximal or mid left anterior descending coronary artery (anterior jeopardy), or in the proximal or mid right coronary artery or proximal circumflex coronary artery in a left dominant circulation (inferior jeopardy). Patients with non-Q-wave anterior infarctions had a significant increase in the frequency of jeopardized myocardium when compared with patients with Q-wave inferior or anterior infarctions. The group with non-Q-wave anterior infarction also had a significantly lower percentage of myocardial segments with absent wall motion in the area of infarction than all other groups. This combination of coronary narrowing with retained wall motion may contribute to the increased frequency of reinfarction seen in some studies of non-Q-wave infarction.

An example of expert systems applied to clinical trials: analysis of serial graded exercise ECG test data.

Clinical trials collect large amounts of data over time. The use of statistical methods to compare and interpret these serial data often fall short of complete evaluation because the analysis requires clinical judgment. As an alternative, some trials use individual experts or panels of experts to evaluate data, but this method usually requires the participation of clinicians who must spend large amounts of time performing tedious, repetitive tasks. The authors examined the use of expert systems to analyze serial clinical trial data where the analyses required use of clinical judgment. A prototype expert system was built to assess the data obtained from a pair of serial graded exercise ECG tests and reach a decision that would duplicate the decision reached by a cardiologist. The experiment was successful. Expert systems should be further developed and tested in other areas, such as serial coronary arteriography data.

Coronary artery atherosclerosis observed in men over 14 consecutive years.

The incidence of cardiovascular death and myocardial infarction associated with ischemic heart disease has declined over the past 15 years. Whether this is associated with a decrease in the severity of coronary atherosclerosis is unknown. The extent of coronary atherosclerosis in men was determined by postmortem coronary angiography in 505 patients over an observation period of 14 years. Patients were divided into those with ischemic heart disease (42%) and those without (58%). Mean coronary scores showed no significant trends over the 14-year period in those without ischemic heart disease and for the last 10 years in those with ischemic heart disease. In those few patients evaluated early in the study with ischemic heart disease, a significantly lower coronary score was found compared to subsequent years. This study was performed during an era of declining cardiovascular death rates and a declining incidence of myocardial infarction, and suggests that this decline may relate to favorable changes in pathogenesis rather than to a decrease in extent of coronary atherosclerosis.