David J. Schwartz

Atriopeptins as Cardiac Hormones

P Needleman, SP Adams, BR Cole, MG Currie, DM Geller, ML Michener, CB Saper, D Atriopeptins as cardiac hormones ISSN: 1524-4563 Copyright

Release of atriopeptin in the rat by vasoconstrictors or water immersion correlates with changes in right atrial pressure

Vasopressin, its 1-deamino analog (dAVP), angiotensin II, and phenylephrine, administered intravenously, increased plasma atriopeptin immunoreactivity in chloral hydrate-anesthetized rats. A continuous one hour infusion of either dAVP or phenylephrine caused a sustained elevation in: a) systemic blood pressure; b) right atrial pressure; c) left ventricular end diastolic pressure; and d) plasma atriopeptin immunoreactivity. While continuous infusion of angiotensin II also produced a sustained elevation in left ventricular end diastolic pressure, the changes in right atrial pressure and plasma atriopeptin were only transient. These data suggest that plasma atriopeptin most closely correlates with right atrial pressure. Consistent with this hypothesis, we found that the release of atriopeptin directly correlated with changes in right atrial pressure in anesthetized, water-immersed rats.

Electrocardiographic evolution of posterior acute myocardial infarction: Importance of early precordial ST-segment depression

Precordial ST-segment depression is typically observed in anterior non-Q-wave acute myocardial infarction (AMI), and is generally not regarded as an indication for acute thrombolytic therapy. Of 544 patients with creatine kinase (CK)-MB-confirmed non-Q-wave AMI randomized to the prospective multicenter Diltiazem Reinfarction Study, 50 patients (9.2%) had isolated precordial ST-segment depression of 1 mm or more in 2 or more contiguous precordial electrocardiographic leads (V1-V4). Serial electrocardiograms recorded at study entry (mean 50.5 hours after onset of chest pain), on study day 2, study day 3 and at predischarge showed that in 23 of 50 patients (40%) electrocardiographic evidence of posterior AMI evolved, defined as an R wave of 0.04 second or more in lead V1 and an R:S greater than or equal to 1 in lead V2. In 18 of these 23 patients (78%), posterior AMI had evolved by study day 3, and none had an abnormal reelevation of CK-MB (every 12-hour sampling) for up to 14 days of hospitalization. Compared with the remaining 27 patients who had electrocardiographic features of anterior non-Q-wave AMI only, the 23 with initial precordial ST segment depression in whom posterior AMI developed had significantly higher mean peak CK values (1,051 +/- 172 vs 663 +/- 89 IU, p less than 0.009) and greater mean precordial ST-segment depression in lead V1 (0.28 vs + 0.19 mm, p = 0.01), in lead V2 (1.3 vs 0.26 mm, p = 0.003) and in lead V3 (2.0 vs 0.93 mm, p = 0.0004).(ABSTRACT TRUNCATED AT 250 WORDS)

Importance of continued activation of thrombin reflected by fibrinopeptide A to the efficacy of thrombolysis

Factors responsible for initial success or failure of coronary thrombolysis and persistent recanalization or early reocclusion have not been thoroughly elucidated. Both adequate initial clot lysis and preclusion of rethrombosis are required. Failure may reflect clot lysis followed immediately or somewhat later by rethrombosis. To determine whether differences in the intensity and persistence of the activation of thrombin are determinants of success or failure of recanalization, plasma fibrinopeptide A, a fibrinogen product liberated by thrombin, was serially assayed in 19 patients treated with intravenous streptokinase. In patients exhibiting recanalization (n = 9), plasma fibrinopeptide A decreased after administration of streptokinase but before administration of heparin. In patients without initially apparent recanalization, fibrinopeptide A increased, suggesting ongoing thrombosis, and subsequently decreased promptly after heparin. In patients with initial recanalization followed by overt reocclusion the pattern was different. Despite recanalization, fibrinopeptide A continued to rise markedly. Elevations persisted despite administration of heparin. Thus, inhibition of activation of thrombin is associated with successful recanalization. Conversely, persistent activation of thrombin may be a predisposing factor to both apparent initial failure of recanalization and overt early reocclusion.

Clinical significance and prognostic importance of left ventricular hypertrophy in non-Q-wave acute myocardial infarction.

Left ventricular (LV) hypertrophy is known to be an independent risk factor for cardiac death, but its significance in non-Q-wave acute myocardial infarction (AMI) has not been assessed previously. In a randomized diltiazem-placebo-controlled therapeutic trial of non-Q-wave AMI confirmed by creatine kinase-MB (CK-MB), 126 of 544 patients (23%) exhibited LV hypertrophy using standard voltage criteria. Compared to patients without LV hypertrophy, patients with LV hypertrophy were significantly older (65 vs 60 years, p less than 0.0001) and had smaller peak adjusted CK levels (490 +/- 376 vs 666 +/- 726 IU/liter, p less than 0.001) than patients without LV hypertrophy. Patients with and without LV hypertrophy did not differ significantly in acute mortality during hospitalization, progression to Q waves, reinfarction by CK-MB criteria or angina associated with transient electrocardiographic changes. Compared with patients without LV hypertrophy, those patients with non-Q-wave AMI and LV hypertrophy had a 2-fold higher incidence of reinfarction (24 vs 12%, p less than 0.005) and death (19 vs 9%, p = 0.044) during the first year of follow-up. Multivariate regression analysis revealed that the relative risk of death and reinfarction during the initial year after AMI was increased by a factor of 1.7 and 2.1 among patients with LV hypertrophy, respectively. It was therefore concluded that, although patients with LV hypertrophy and non-Q-wave AMI have smaller enzymatic infarcts and the same short-term prognosis as do patients without LV hypertrophy, their reinfarction and mortality rates are significantly increased during the first year of follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential risk patterns associated with 3 month as compared with 3 to 12 month mortality and reinfarction after non-Q wave myocardial infarction☆

Follow-up data for 515 survivors of acute non-Q wave myocardial infarction were categorized according to mortality: 1) between hospital discharge and 3 months after infarction (early), and 2) between 3 and 12 months after infarction (late). The mortality rate decreased steadily for the first 3 months and was constant thereafter. There were 25 early and 32 late deaths. After adjustment for the longer time associated with the 3 to 12 month period, the relative risk per unit time of early as compared with late mortality was 2.64. Risk factors for early mortality were different from those that predicted late mortality. Independent predictors of mortality between hospital discharge to 3 months after infarction were ST segment depression that persisted during hospitalization (p less than 0.0001), in-hospital reinfarction (p = 0.0006) and a history of congestive heart failure (p = 0.0255). Persistent ST depression and in-hospital reinfarction had neither a univariate nor an independent association with 3 to 12 month mortality. Age (p less than 0.0001), reinfarction between discharge and 3 months (p = 0.0147) and diabetes (p = 0.0404) were independently associated with late mortality. Early mortality was only 0.5% (1 of 199) in patients with no ST depression at either baseline or discharge (group 1); 4.8% (8 of 168) in those with ST depression at exactly one time point (group 2) and 13.7% (16 of 117) in those who had ST depression present at both time points (group 3). All pairwise differences were significant (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

ST segment shifts are poor predictors of subsequent Q wave evolution in acute myocardial infarction. A natural history study of early non-Q wave infarction.

Acute ST segment elevation is regarded generally as the sine qua non of evolving Q wave myocardial infarction (MI) because such electrocardiographic (ECG) injury is believed to be a marker of transmural ischemia and a forerunner of transmural necrosis. Alternatively, ST segment depression with or without T wave inversion is viewed as the dominant ECG feature of non-Q wave MI. However, this hypothesis has not been assessed prospectively in an acute MI population. We analyzed 2,304 serial ECGs at study entry (admission), day 2, day 3, and predischarge (mean, 10.2 +/- 2 days) from 576 patients with creatine kinase MB confirmed acute non-Q wave MI to determine what percentage of patients with early ST segment elevation culminated in subsequent Q wave development. Of this group, 187 patients (32%) exhibited 1 mm or greater ST segment elevation in two or more contiguous entry ECG leads. Of those patients whose non-Q wave MI could be localized on the basis of diagnostic admission ST segment shifts, the prevalence of early ST segment elevation was 43% (187 of 439). The sum total mean (+/- SD) peak ST segment elevation by lead group (anterior, inferior, lateral) was 4.0 +/- 2.4, 4.5 +/- 2.4, and 2.5 +/- 0.6 mm, respectively. Despite this, only 20% of patients with ST segment elevation (37 of 187) developed Q waves. Of 252 patients who exhibited early ST segment depression or T wave inversion or both, 39 (15%) evolved subsequent Q waves. Thus, while the prevalence of early ST segment elevation in acute evolving non-Q wave MI was higher than previously reported, 80% of patients with and 85% of patients without ST segment elevation and absent Q waves on the admission ECG did not develop subsequent Q waves during a 2-week period of observation (p = NS). In addition, when patients with ST segment elevation were compared with patients with ST segment depression or T wave inversions or both, there were no between-group differences in log peak creatine kinase (404 vs. 383 IU), reinfarction (6% vs. 8%), postinfarction angina (50% vs. 42%), or early recurrent ischemia (49% vs. 45%), defined as postinfarction angina with transient ECG changes. Thus, in patients who present with initial acute non-Q wave MI, ST segment shifts on admission are unreliable predictors of subsequent Q wave evolution and do not discriminate significant differences in postinfarction outcome. In particular, ST segment elevation during the early hours of evolving infarction is not an invariable harbinger of subsequent Q wave development.

Frequency and significance of late evolution of Q waves in patients with initial non-Q-wave acute myocardial infarction

Serial 12-lead electrocardiogram and plasma creatine kinase (CK)-MB values from 544 patients with confirmed non-Q-wave acute myocardial infarction (AMI) were analyzed to define the rate of progression of non-Q-wave AMI to Q-wave AMI and to examine its relation to CK-MB evidence of extension. The baseline electrocardiogram was obtained 50 +/- 10 hours after AMI and compared with subsequent electrocardiograms at 48 and 72 hours after baseline record and at discharge. Plasma CK-MB was assayed every 12 hours after baseline. A total of 76 patients (14%) progressed to Q-wave AMI. Compared to the 468 patients who retained non-Q-wave AMI, those patients who evolved Q-wave AMI were more likely to exhibit ST elevation greater than or equal to 1.0 mm in greater than or equal to 2 infarct-related leads (49 vs 32%, p less than 0.005), higher peak CK values with the index AMI (754 +/- 625 vs 611 +/- 604 IU; p = 0.0018) and a greater incidence of CK-MB-confirmed extensions (18.5 vs 5.5%, p less than 0.0001). For those patients progressing to Q-wave AMI within 48 hours of baseline electrocardiogram, CK-MB extension occurred in 9.5% (4 of 42) versus 29.4% (10 of 34) of those who progressed after 48 hours (p = 0.0262). A distinct minority (14%) of patients with non-Q-wave AMI will develop Q waves before discharge. The progression to Q-wave AMI after initial non-Q-wave AMI appears to involve 2 different mechanisms: temporal lag in the electrocardiogram, and actual extension by quantitative CK-MB criteria.

Atriopeptin release in conditions of altered salt and water balance in the rat

Manipulations of salt and water intake influenced the atriopeptin content in the atria and plasma of rats. Plasma levels of atriopeptin varied in proportion with dietary salt intake. In contrast, cardiac levels of atriopeptin varied inversely with the amount of salt in the diet. Acute stimulation of atriopeptin release can be produced by treatments which elevate atrial pressure, including atrial stretch, volume overloading, water immersion, and vasoconstrictor agents. Vasopressin-stimulated atriopeptin release preferentially depleted right atrial stores. In spite of the initial differences in cardiac stores of atriopeptin in the rats on different diets, there were no major differences in the amount of atriopeptin released in response to vasopressin stimulation. These data suggest that there is a functional excess of cardiac atriopeptin stores. We also examined the atrial and plasma atriopeptin content in the Dahl salt-sensitive and resistant rats to determine whether the development of hypertension in the Dahl sensitive rats is associated with abnormalities in basal or stimulated levels of atriopeptin. The effects of dietary salt intake on basal and stimulated atriopeptin levels in both the Dahl sensitive and resistant rats were similar to those observed in normal rats, suggesting that abnormalities in atriopeptin content do not contribute to the etiology of hypertension in the Dahl salt-sensitive rat.

Favourable long term prognosis in patients with non-Q wave acute myocardial infarction not associated with specific electrocardiographic changes. Diltiazem Reinfarction Study Research Group.

Electrocardiograms obtained serially from 544 patients with non-Q wave infarction in the Diltiazem Reinfarction Study were analysed to compare the short term (less than or equal to 14 days) and long term (one year) follow up of 105 patients (19%) whose admission electrocardiogram showed no localisable repolarisation abnormalities (group 1) with the outcome in 439 patients (81%) who had ST-T wave abnormalities (group 2) localised to two or more contiguous leads within an anterior, inferior, or lateral lead group. There were no major between group differences in baseline clinical variables, concomitant medications, or treatment allocation (diltiazem v placebo). Group 2 patients, in the first year, had a higher incidence of early recurrent ischaemia (angina greater than or equal to 24 hours after myocardial infarction associated with ischaemic repolarisation changes), reinfarction, and readmission for chest pain than group 1 patients, despite comparable creatine kinase and creatine kinase MB activities in both groups. About 20% of patients with acute non-Q wave myocardial infarction did not have definable ST-T wave abnormalities. These patients had a similar clinical and enzymatic profile as patients with non-Q wave infarction with definable ST-T wave abnormalities and they were more likely to have a favourable short term and long term outcome.