John O. Parker

Cardiovascular Death and Left Ventricular Remodeling Two Years After Myocardial Infarction Baseline Predictors and Impact of Long-term Use of Captopril: Information From the Survival and Ventricular Enlargement (SAVE) Trial

BACKGROUND We quantified cardiovascular death and/or left ventricular (LV) dilatation in patients from the SAVE trial to determine whether dilatation continued beyond 1 year, whether ACE inhibitor therapy attenuated late LV dilatation, and whether any baseline descriptors predicted late dilatation. METHODS AND RESULTS Two-dimensional echocardiograms were obtained in 512 patients at 11+/-3 days and 1 and 2 years postinfarction to assess LV size, percentage of the LV that was akinetic/dyskinetic (%AD), and LV shape index. LV function was assessed by radionuclide ejection fraction. Two hundred sixty-three patients (51.4%) sustained cardiovascular death and/or LV diastolic dilatation; 279 (54.5%) had cardiovascular death and/or systolic dilatation. In 373 patients with serial echocardiograms, LV end-diastolic and end-systolic sizes increased progressively from baseline to 2 years (both P<.01). More patients with LV dilatation had a decrease in ejection fraction: 24.8% versus 6.8% (P<.001) (diastole) and 25.7% versus 5.3% (P<.001) (systole). Captopril attenuated diastolic LV dilatation at 2 years (P=.048), but this effect was carried over from the first year of therapy because changes in LV size with captopril beyond 1 year were similar to those with placebo. Predictors of cardiovascular death and/or dilatation were age (P=.023), prior infarction (P<.001), lower ejection fraction (P<.001), angina (P=.007), heart failure (P=.002), LV size (P<.001), and infarct size (%AD) (P<.001). CONCLUSIONS Cardiovascular death and/or LV dilatation occurred in >50% of patients by 2 years. LV dilatation is progressive, associated with chamber distortion and deteriorating function that is unaffected by captopril beyond 1 year.

A comparison of management patterns after acute myocardial infarction in Canada and the United States

BACKGROUND There are major differences in the organization of the health care systems in Canada and the United States. We hypothesized that these differences may be accompanied by differences in patient care. METHODS To test our hypothesis, we compared the treatment patterns for patients with acute myocardial infarction in 19 Canadian and 93 United States hospitals participating in the Survival and Ventricular Enlargement (SAVE) study, which tested the effectiveness of captopril in this population of patients after a myocardial infarction. RESULTS In Canada, 51 percent of the patients admitted to a participating coronary care unit had acute myocardial infarctions, as compared with only 35 percent in the United States (P < 0.001). Despite the similar clinical characteristics of the 1573 U.S. patients and 658 Canadian patients participating in the study, coronary arteriography was more commonly performed in the United States than in Canada (in 68 percent vs. 35 percent, P < 0.001), as were revascularization procedures before randomization (31 percent vs. 12 percent, P < 0.001). During an average follow-up of 42 months, these procedures were also performed more commonly in the United States than in Canada. These differences were not associated with any apparent difference in mortality (22 percent in Canada and 23 percent in the United States) or rate of reinfarction (14 percent in Canada and 13 percent in the United States), but there was a higher incidence of activity-limiting angina in Canada than in the United States (33 percent vs. 27 percent, P < 0.007). CONCLUSIONS The threshold for the admission of patients to a coronary care unit or for the use of invasive diagnostic and therapeutic interventions in the early and late periods after an infarction is higher in Canada than in the United States. This is not associated with any apparent difference in the rate of reinfarction or survival, but is associated with a higher frequency of activity-limiting angina.

Oral Isosorbide dinitrate in angina pectoris: Comparison of duration of action and dose-response relation during acute and sustained therapy

The effects of different oral doses of isosorbide dinitrate administered acutely and four times daily during sustained therapy were studied in 12 patients with angina pectoris. After administration of 30, 60 and 120 mg of isosorbide dinitrate, the average plasma concentrations were higher and the area under the plasma concentration time curve was greater during sustained than during acute therapy (p less than 0.01). Reduction in standing systolic blood pressure was greater during acute than during sustained therapy (p less than 0.001). This reduction in systolic blood pressure was dose-related and persisted for 8 hours during acute therapy, but was not dose-related and was demonstrable for only 4 hours during sustained therapy. Compared with placebo therapy, exercise duration to the onset of angina and to the development of moderate angina increased significantly after each dose of isosorbide dinitrate for 8 hours during acute therapy but for only 2 hours during sustained therapy. During acute therapy, administration of a single dose of 15 or 30 mg of isosorbide dinitrate produced similar improvement in exercise tolerance as did a dose of 60 or 120 mg. During sustained therapy (15 mg four times daily), exercise tolerance increased to the same magnitude as with doses of 30, 60 or 120 mg four times daily. In most patients, near maximal improvement in exercise tolerance occurred after a dose of 15 or 30 mg four times daily. It is concluded that during sustained therapy with isosorbide dinitrate, partial tolerance to the antianginal and circulatory effects develops rapidly.

Prognostic value of neurohumoral activation in patients with an acute myocardial infarction: effect of captopril.

OBJECTIVES This study attempted to evaluate whether neurohumoral activation at the time of hospital discharge in postinfarction patients helps to predict long-term prognosis and whether long-term therapy with the angiotensin-converting enzyme inhibitor captopril modifies this relation. BACKGROUND Neurohumoral activation persists at the time of hospital discharge in a large number of postinfarction patients. The Survival and Ventricular Enlargement (SAVE) study demonstrated that the angiotensin-converting enzyme inhibitor captopril improves survival and decreases the development of severe heart failure in patients with left ventricular dysfunction (left ventricular ejection fraction < or = 40%) but no overt postinfarction heart failure. METHODS In 534 patients in the SAVE study, plasma neurohormone levels were measured a mean of 12 days after infarction. Patients were then randomized to receive captopril or placebo and were followed up for a mean (+/- SD) of 38 +/- 6 months (range 24 to 55). The association between activation of plasma neurohormones at baseline and subsequent cardiovascular mortality or the development of heart failure was assessed with and without adjustment for other important prognostic factors. RESULTS By univariate analysis, activation of plasma renin activity and aldosterone, norepinephrine, atrial natriuretic peptide and arginine vasopressin levels were related to subsequent cardiovascular events, whereas epinephrine and dopamine levels were not. By multivariate analysis, only plasma renin activity (relative risk 1.6, 95% confidence interval [CI] 1.0 to 2.5) and atrial natriuretic peptide (relative risk 2.2, 95% CI 1.3 to 3.8) were independently predictive of cardiovascular mortality, whereas the other neurohormones were not. Only plasma renin activity and aldosterone, atrial natriuretic peptide and arginine vasopressin were independent predictors of the combined end points of cardiovascular mortality, development of severe heart failure or recurrent myocardial infarction. Except for 1-year cardiovascular mortality, the use of captopril did not significantly modify these relations. CONCLUSIONS Neurohumoral activation at the time of hospital discharge in postinfarction patients is an independent sign of poor prognosis. This is particularly true for plasma renin activity and atrial natriuretic peptide. Except for 1-year cardiovascular mortality, captopril does not significantly modify these relations.

Hemodynamics at rest and during supine and sitting bicycle exercise in normal subjects

Abstract To assess left ventricular function and to compare mean pulmonary wedge pressure and left ventricular end-diastolic pressure in the supine and sitting positions, 10 patients without demonstrable cardiovascular disease underwent hemodynamic studies at rest and during exercise In the two positions. At rest the values for heart rate were higher and the values for cardiac index, stroke index, left ventricular stroke work Index, mean pulmonary capillary wedge pressure and left ventricular end-diastolic pressure were lower in the sitting position. During both supine and sitting exercise left ventricular end-diastolic pressure, cardiac index, stroke index and left ventricular stroke work index increased significantly from the resting values. Comparison of data during exercise revealed higher values for heart rate and rate-pressure product and lower values for pulmonary capillary wedge pressure, left ventricular end-dlastollc pressure and stroke index in the sitting position; systolic and mean systemic pressure, cardiac index and left ventricular stroke work Index were similar during the two exercise periods. When absolute changes from rest to exercise were compared, the Increase In heart rate, systolic blood pressure, pulmonary capillary wedge pressure, left ventricular end-dlastollc pressure, cardiac index, stroke index, and left ventricular stroke work index were similar In the two positions. There was a good correlation between left ventricular end-diastolic pressure and pulmonary capillary wedge pressure at rest and during exercise in the two postures.

Effect of Intervals between Doses on the Development of Tolerance to Isosorbide Dinitrate

We studied the development of tolerance to isosorbide dinitrate in 12 patients with chronic stable angina pectoris. The effect of 30 mg of isosorbide dinitrate on treadmill exercise performance was assessed before and at one, three, and five hours after a single dose. As compared with placebo, the drug increased treadmill walking time until the onset of angina and until the development of moderate angina over the five-hour observation period (P less than 0.05). The patients then received 30 mg of isosorbide dinitrate twice, three times, and four times daily for a period of one week, and exercise performance was assessed before and at one, three, and five hours after the final morning dose. During sustained treatment two and three times daily, treadmill walking time was longer throughout the five-hour testing period than during the placebo phase (P less than 0.05). In contrast, during treatment four times daily, treadmill walking time was prolonged at one hour (P less than 0.05) but not at three and five hours after the last dose. We conclude that tolerance to the clinical effects of isosorbide dinitrate develops with a sustained dosage of 30 mg four times daily, but not when the drug is given two or three times daily.

Counter-regulatory responses to continuous and intermittent therapy with nitroglycerin.

BackgroundVasodilator therapy may be associated with reflex counter-regulatory responses, and these responses may play a role in the development of tolerance to nitroglycerin (GTN). Methods and ResultsStanding systolic blood pressure, body weight, urinary sodium, and hormonal responses to continuous (n = 10) and intermittent (n = 10) transdermal GTN administration were studied in normal volunteers. There was rapid attenuation of the hypotensive response to transdermal GTN therapy in the continuous but not in the intermittent therapy group. Significant weight gain and sodium retention occurred during continuous but not during intermittent GTN therapy. This was accompanied by a greater decrease in hematocrit in the continuous group, a finding that suggests that plasma volume expansion occurred during continuous GTN therapy. Continuous GTN therapy was associated with increases in plasma norepinephrine, atrial natriuretic peptide, arginine, vasopressin, and plasma renin activity. A different pattern of neurohormonal response was seen during intermittent therapy, with values tending to return to baseline levels after the nitrate-free interval. ConclusionsContinuous transdermal GTN therapy leads to counter-regulatory responses associated with sodium retention and probable plasma volume expansion. By contrast, intermittent transdermal GTN therapy is associated with a different pattern of hormonal response, the lack of sodium retention and no evidence of plasma volume expansion. It is likely that these counter-regulatory responses play an important role in the attenuation of nitrate effects.

Tolerance to the circulatory effects of oral isosorbide dinitrate: Rate of development and cross tolerance to glyceryl trinitrate

The effects of 15, 30, 60 and 120 mg of isosorbide dinitrate (ISDN) on systolic blood pressure (SBP) and heart rate (HR) were compared after acute oral administration and during sustained therapy four times daily with ISDN in six patients. After any given dose, plasma ISDN levels were higher during sustained therapy than during acute therapy. The average peak reduction in standing SBP occurred at 2 hours after 15, 30, 60 and 120 mg of ISDN; the values were 39, 42, 45 and 46 mm Hg, respectively, after acute therapy and 21, 20, 26 and 24 mm Hg, respectively, during sustained therapy (p < 0.01). Compared with placebo, the reduction in SBP was still apparent 6 hours after any given dose of ISDN during acute but not during sustained therapy (p < 0.01). HR increased significantly only after acute therapy.The rapidity of development of tolerance to ISDN and cross–tolerance to glyceryl trinitrate (GTN) was evaluated in eight other patients. The average peak reduction in SBP after the first dose of 15 mg of ISDN was 36 mm Hg, but after therapy with ISDN every 6 hours, the fifth dose of 15 mg of ISDN produced a peak reduction in SBP of only 7 mm Hg (p < 0.001). The first dose of 0.6 mg GTN before therapy with ISDN produced a peak reduction in SBP of 40 mm Hg, but after therapy with ISDN every 6 hours for 5 days, the same dose of GTN produced a maximum reduction in SBP of only 10 mm Hg (p < 0.001).The results show that partial circulatory tolerance to ISDN and cross–tolerance to GTN developed rapidly during regular therapy with ISDN. The plasma ISDN concentrations were higher during sustained than after acute therapy, suggesting that the tolerance (tachyphylaxis) to nitrates in man is due to the diminution of the end organ response and not to the accelerated metabolism of nitrates.

A hemodynamic study of acute coronary insufficiency precipitated by exercise: With observations on the effects of nitroglycerin

Abstract Twenty-four patients with coronary artery disease and 10 normal subjects were studied at rest and exercise. All patients with coronary artery disease experienced pain of acute coronary insufficiency during exercise, and hemodynamic abnormalities indicative of impaired left ventricular function developed. Eleven of the 14 patients with coronary artery disease who were studied after nitroglycerin administration were able to perform an identical exercise without chest pain and with no associated hemodynamic abnormalities. The exact mechanism of action of nitroglycerin is uncertain, but it is suggested that it may act by decreasing myocardial oxygen needs through a reduction of left ventricular volume.

Reversible Cardiac Failure During Angina Pectoris Hemodynamic Effects of Atrial Pacing in Coronary Artery Disease

Left ventricular end-diastolic pressure and left ventricular stroke work were measured during a 10-min period of atrial pacing in 10 normal subjects and 30 patients with coronary artery disease. The normal subjects and the patients with coronary artery disease who did not experience angina during pacing reacted similarly with a fall in left ventricular end-diastolic pressure from 8 to 2 mm Hg returning to control values on cessation of pacing. The average left ventricular end-diastolic pressure during pacing in the 21 patients who developed angina was similar to control values although this pressure rose to abnormal levels in four patients. On cessation of pacing the left ventricular end-diastolic pressure rose abruptly to an average value of 22 mm Hg. This lack of elevation of filling pressure during pacing and the rise to abnormal levels on termination of pacing can best be explained by relating left ventricular end-diastolic pressure to left ventricular stroke work. Analyzed in this fashion it is evident that the ischemic ventricle is operating on a depressed ventricle function curve. This depression of function is reversible following cessation of pacing and can be prevented by the prior administration of nitroglycerin.