Cardiac natriuretic peptides and continuously monitored atrial pressures during chronic rapid pacing in pigs.

Changes in atrial natriuretic peptide (ANP), N-terminal proatrial natriuretic peptide and brain natriuretic peptide (BNP) were evaluated in relation to continuously monitored atrial pressures in a pacing model of heart failure. Pigs were subjected to rapid atrial pacing (225 beats min-1) for 3 weeks with adjustments of pacing frequencies if the pigs showed overt signs of cardiac decompensation. Atrial pressures were monitored by a telemetry system with the animals unsedated and freely moving. Left atrial pressure responded stronger and more rapidly to the initiation of pacing and to alterations in the rate of pacing than right atrial pressure. Plasma natriuretic peptide levels were measured by radioimmunoassay and all increased during pacing with BNP exhibiting the largest relative increase (2.9-fold increase relative to sham pigs). Multiple regression analysis with dummy variables was used to evaluate the relative changes in natriuretic peptides and atrial pressures and the strongest correlation was found between BNP and left atrial pressure with R 2=0.81. Termination of pacing resulted in rapid normalization of ANP values in spite of persistent elevations in atrial pressures. This may reflect an increased metabolism or an attenuated secretory response of ANP to atrial stretch with established heart failure. In conclusion, 3 weeks of rapid pacing induced significant increases in atrial pressures and natriuretic peptide levels. All the natriuretic peptides correlated with atrial pressures with BNP appearing as a more sensitive marker of cardiac filling pressures than ANP and N-terminal proatrial natriuretic peptide.

Power of plasma N-terminal proatrial natriuretic factor to determine haemodynamics in patients with cardiac disease: relation to serum creatinine.

OBJECTIVE: The aim was to examine the usefulness of plasma N-terminal proatrial natriuretic factor (N-terminal proANP) as a non-invasive marker of cardiac pressure in patients with normal to mildly elevated serum creatinine. METHODS: Blood samples were drawn at rest from 100 patients with cardiac disease undergoing diagnostic cardiac catheterization. RESULTS: Using multivariate analysis, N-terminal proANP was independently related to mean pulmonary capillary wedge pressure (PCWP), mean right atrial pressure, serum creatinine (s-creatinine) and cardiac index. These indices accounted for about 50% of the variation in N-terminal proANP. All patients with N-terminal proANP < 1000 pmol/l had normal PCWP (< 13 mmHg). Areas under the receiver-operating characteristic (ROC) curves for N-terminal proANP for the detection of PCWP > or = 13, > or = 18 and > or = 24 mmHg were 0.903, 0.870 and 0.876, respectively. CONCLUSION: These results suggest that analysis of plasma N-terminal proANP is a simple and powerful method for assessing cardiac pressure in patients with heart disease and normal and mildly elevated s-creatinine (< 165 micromol/l). The value of N-terminal proANP cannot, however, indiscriminately be used to assess cardiac haemodynamics. N-terminal proANP measurement is a useful screening parameter for identifying patients with normal cardiac pressures.

According to MIAMI and ISIS-I trials, can a general recommendation be given for beta blockers in acute myocardial infarction?

The goal of early intervention of acute coronary occlusion by beta blockers is to reduce ultimate infarct size and to consequently reduce morbidity and mortality. Until 1986 small early intervention trials suggested that infarct size may be reduced by 25% if treatment was started within 6 to 10 hours after the onset of symptoms. At this time, an average of 80% of the infarct is fully developed. On the basis of previous trials, the reduction of infarct size has been associated with improvement of symptoms, prevention of infarct development, reduced occurrence of arrhythmias and reinfarctions, and earlier discharge from the hospital. Although the trials suggested some benefit in mortality, this issue has not been solved. The MIAMI trial randomized 5778 patients to blind treatment with metoprolol or placebo. ISIS-I randomized 16,027 patients to atenolol with an open label. No titration of the effect on lowering myocardial oxygen requirement was attempted. Both studies included less than 25% of all eligible patients. Exclusions were chiefly due to current beta blocker or calcium blocker treatment. Thus, the results obtained concern only a selected group of patients. In MIAMI only 15% received treatment within 6 hours, while in ISIS 38% were treated within 4 hours. It is therefore likely that in most patients the infarcts were completed before intervention was started. Thus, the two trials did not differentiate between primary and secondary effects on the acute myocardial infarct. Mortality was reduced by 13% (NS) and 15% (p less than 0.04), respectively, in MIAMI and ISIS.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitative and temporal relation between the release of myoglobin and creatine kinase and the evolution of vectorcardiographic changes during acute myocardial infarction in man.

The relation in time and magnitude between QRS vector changes (QRS-VD), ST vectors (ST-VM), and the cumulated release of myoglobin, total creatine kinase, and creatine kinase isoenzyme MB was studied. Seventy four patients with a first myocardial infarction and a history of symptoms of up to 5 h were included. Blood samples for enzyme analysis were taken every 4-6 h for 72 h and cumulated enzyme release was calculated from a monocompartmental first order model. QRS-VD and ST-VM were determined every 10 min for 24 h by computer analysis of Frank lead vectorcardiograms. Infarct sizes were visually determined from the different enzymatic and vectorcardiographic evolution curves. Eight patients were excluded from the analysis because they had a QRS width greater than or equal to 120 ms or ill defined plateaus of the release curves. The relation between infarct sizes estimated from QRS-VD and total creatine kinase was r = 0.62; QRS-VD and myoglobin release r = 0.57; total creatine kinase and myoglobin release r = 0.72, showing that these variables are good and complementary indices for estimating myocardial infarct size. Median infarct evolution curves were computed after the individual curves were normalised to 100%. ST-VM fell rapidly during the first 7 h to 40% of the initial values. QRS-VD and myoglobin release were closely associated and completed their development on average 15 h after the onset of symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Fever after acute myocardial infarction in patients treated with intravenous timolol or placebo.

Body temperature was studied in 65 patients admitted to hospital within four hours of the onset of symptoms of acute myocardial infarction. Thirty three patients had been randomly assigned to intravenous timolol treatment and 32 to placebo treatment. Infarct evolution was assessed by continuous vectorcardiography and creatine kinase release. Maximum and mean temperatures during the first eight days were significantly lower in the timolol group, who were discharged from hospital one day earlier. Eight patients in the placebo group had temperatures of greater than 39 degrees compared with one in the timolol group. Both the mean temperature and the maximum temperature correlated significantly with indices of infarct size and ischaemic area as estimated by cumulative creatine kinase release, QRS vector difference, and ST vector magnitude. The results were consistent with the view that reduction of infarct size may partly explain the reduced pyrexial response after timolol treatment. Other mechanisms are probably also involved in larger infarcts. Because high fever has detrimental haemodynamic effects in acute myocardial infarction, reduction of this response may be beneficial. The results support the early use of beta adrenoceptor blockade in acute myocardial infarction.

A comparison of cumulated CK release with three vectorcardiographic methods of estimating myocardial infarct size.

Infarct size estimated by three vectoracardiographic methods was compared with cumulated CK release in 66 patients admitted to hospital within five hours after onset of myocardial infarction. Infarctional changes in the QRS complex were sequentially computed from a continuous 24-hour recording of Frank lead VCG by: (I)-the integrals of QRS vector differences (QRS-VD) relative to the first recording obtained after hospitalization, (II)-the integral of spatial magnitude during the period of initial abnormal depolarization (IAD), (III)-The sum of R-wave amplitude in leads X and Y and Q-wave amplitude in lead Z (sigma R). From the time-trend curves of cumulated CK release, QRS-VD, IAD and sigma R terminal plateau levels were visually determined representing estimated infarct size (ISCK, ISQRS-VD, ISIAD and IS sigma R). The correlation coefficients were: between ISCK and ISQRS-VD r = 0.62, p less than 0.001, ISCK and ISIAD r = 0.22, p = NS, ISCK and IS sigma R r = -0.22, p = NS. The correlation for ISQRS-VD was significantly better than for ISIAD (p = 0.011) and IS sigma R (p = 0.005). The IAD time-trend curves were inconsistent, falling in 24 and rising in 24 patients. For sigma R the corresponding figures were 56 and 10 patients. Thus, neither IAD nor sigma R have been shown to predict infarct size correctly at an early stage or to describe infarct evolution adequately.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of timolol on mortality and reinfarction after acute myocardial infarction: prognostic importance of heart rate at rest.

Long-term timolol treatment after acute myocardial infarction is associated with a significant reduction in mortality and nonfatal reinfarction. To evaluate whether the reduction in mortality and morbidity is exclusively or partly dependent on a reduction in heart rate (HR), cardiac events in the Norwegian Timolol Multicenter Study were analyzed according to resting HR at baseline and at 1 month of follow-up Resting HR at baseline was a significant predictor of total death and all events (total death plus nonfatal reinfarction) both in placebo- and in timolol-treated patients. In the placebo group the median resting HR was unchanged from baseline to 1 month control (72 beats/min), but was reduced from 72 beats/min to 56 beats/min in the timolol group. Resting HR during follow-up remained a significant predictor of total death. Further, mortality at a given HR during treatment was not markedly different whether the HR was spontaneous or caused by timolol. Timolol treatment was related to a significant reduction in mortality, and this study suggests that the major effect of timolol treatment on mortality after acute myocardial infarction may be attributed to the reduction in HR. Timolol treatment was also associated with an overall reduction in nonfatal reinfarction. However, nonfatal reinfarction was inversely related to resting HR during follow-up, indicating that although coronary artery occlusion in low-risk patients may cause nonfatal reinfarction, the outcome in high-risk patients is more likely to be death. When analyzing mortality and nonfatal reinfarction combined, timolol treatment was related to a reduction in cardiac events at any given HR, suggesting that factors in addition to HR reduction are important in the protective effects of timolol.

Importance of heart rate in determining beta-blocker efficacy in acute and long-term acute myocardial infarction intervention trials.

Heart rate after an acute myocardial infarction (AMI) is an index of late mortality. The hypothesis--that the potential beneficial effect of beta-blocking drugs after an AMI is quantitatively dependent on the reduction of heart rate obtained by such treatment--was examined by reviewing available data from acute and long-term intervention trials. Only properly randomized and double-blind trials were considered. In acute intervention trials only patients who received treatment within 12 hours after onset of pain were included. In early intervention trials there was a close relation between the reduction in heart rate and infarct size as determined by accumulated creatine kinase release (r = 0.97, p less than 0.001). A reduction in heart rate of at least 15 beats/min during infarct evolution was associated with a reduction of infarct size between 25 and 30%. The data suggest that a reduction in heart rate less than 8 beats/min has no effect or may actually increase infarct size. Comparison of post-AMI trials indicated a relation between the actual reduction of resting heart rate and percentage of reduction in mortality obtained in each trial (r = 0.60, p less than 0.05). An almost similar relation was demonstrated between the reduction in resting heart rate and nonfatal reinfarctions (r = 0.59, p less than 0.05). Confounding properties of a beta blocker, such as intrinsic sympathomimetic activity or prolongation of the QT interval, may reduce its efficacy. These results strongly suggest that the beneficial effect of beta blockers is related to a quantitative reduction in heart rate, probably indicating an antiischemic effect. However, the data do not exclude the possibility that other protective mechanisms may be operative.

Evolution of vectorcardiographic QRS changes during myocardial infarction in dogs and their relation to infarct size.

The ability of vectorcardiographic QRS changes to quantify myocardial ischaemia and necrosis in dogs was studied. Myocardial infarction was produced in 21 anaesthetised dogs by inflating a balloon inserted into the right, left anterior descending, or left circumflex coronary artery. A Frank vectorcardiogram was recorded before and every 15-30 minutes for 10 hours after the occlusion. ST vector magnitude (ST-VM), QRS summation vectors, and QRS integral differences (QRS-VD) between the preocclusion recording and subsequent recordings were computed. Twenty four hours after occlusion two vectorcardiograms were obtained, the hearts removed, and the infarcts cut out and weighed. Four dogs were excluded from the study because of persistent arrhythmias, major conduction defects, or sudden death. In the remaining 17 dogs the QRS summation vectors rotated maximally towards the site of infarction 7 minutes after occlusion corresponding to a median minimum QRS-VD of -19 (range -2 to -29) microVs. This coincided with the maximum ST-VM, median 0.43 (range 0.12-0.68) mV. The QRS summation vectors subsequently rotated away from the infarct producing a median maximum QRS-VD of 20 (range 6-28) microVs. The maximum QRS-VD correlated significantly with the percentage of infarcted myocardium (r = 0.82). The correlation between the early minimum QRS-VD and the maximum ST-VM was r = 0.83. The QRS-VD was recomputed with a reference taken 2 or 4 hours after occlusion. The relation between maximum QRS-VD and infarct percentage was not significantly changed with the reference at 2 hours, but with the reference at 4 hours the ability to predict infarct size was lost.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary blood flow and myocardial segment dimensions during simulated dives in seals.

Three harbor seals Phoca vitulina richardsi and five spotted seals Phoca vitulina largha were used in studies of acute episodes of local myocardial ischemia in open-chest, anesthetized animals and of coronary blood flow and regional function as indicated by left ventricular segment dimensions during experimentally simulated dives of conscious, instrumented animals. We observed that seal myocardium, in which there are few coronary anastomoses, responded to brief local occlusion with prompt local dysfunction and systolic bulging; coronary flow in the nondiving seal oscillated irregularly and declined with spontaneous apnea and related falling heart rate; flow continued to oscillate but was much reduced during dives, frequently ceasing entirely for periods as long as 45 s; ventricular segment dimension shortening was reduced intermittently during dives; and elevated heart rate induced during dives by cardiac pacing or by administration of atropine diminished or eliminated the reductions in coronary blood flow. Responses of seal heart reflect the reduction in cardiac metabolic demand during diving and the seal's myocardial adaptation for enhanced anaerobic glycolysis. The seal heart can maintain mechanical function during dives with minimal coronary perfusion, despite the progressive and ultimately profound hypoxia, hypercapnia, and acidosis. Reduced cardiac metabolism, copious glycolytic reserves, and metabolite washout by intermittent brief bursts of coronary blood flow are apparently sufficient to support continued cardiac function, even though the seal heart has little tolerance for acute localized ischemia.

Evolution of infarct size during the early use of nifedipine in patients with acute myocardial infarction: the Norwegian Nifedipine Multicenter Trial.

In a multicenter double-blind study, 227 patients with suspected acute myocardial infarction (AMI) were randomized within 12 hr from onset of symptoms to treatment with nifedipine (112 patients) or placebo (115 patients). AMI was confirmed in 74 patients on nifedipine and in 83 on placebo. Patients with AMI received nifedipine 5.5 +/- 2.9 hr (mean +/- SD) after onset of symptoms. Infarct size was assessed by the release of creatine kinase isoenzyme MB (CK-MB). Infarct size index (CK-MB geq/m2) was 25 +/- 16 (n = 71) in the nifedipine group and 23 +/- 13 (n = 77) in the placebo group (NS). After the first 10 mg of nifedipine systolic blood pressure fell from 147 +/- 30 to 135 +/- 28 mm Hg (p less than .01) and heart rate rose from 75 +/- 18 to 79 +/- 19 beats/min (p less than .01). No change was observed after the first placebo dose. The treatment was continued for 6 weeks. Over this period there were 10 deaths in each group. Early treatment with nifedipine in patients with AMI does not seem to reduce infarct size as determined by enzyme level.

Acute and long-term response to enalapril in congestive failure.

Enalapril, a novel long acting angiotensin converting enzyme (ACE) inhibitor, was given orally to 12 patients with chronic heart failure (NYHA functional class III and IV) and cardiomegaly. The optimal dose averaged 17 mg given once-daily. Heart rate, systemic arterial blood pressure, pulmonary arterial pressure, right and left ventricular filling pressures and cardiac index were monitored during dose efficacy titration. Eleven patients were recatheterised 3 months later. After stabilisation of cardiac filling pressures, all patients had left ventricular filling pressures in excess of 20 mmHg. Enalapril increased cardiac index acutely by 34% but at 12 weeks follow-up, cardiac index was not different from control levels. Left ventricular filling pressure was reduced acutely by 36% and by 41% at 3 months. Heart rate, systemic arterial and right atrial pressures and plasma concentrations of aldosterone were reduced during the observation period. ACE activity was inhibited at the time of peak haemodynamic effect from 25.3 +/- 9.8 to 4.9 +/- 3.4 U/ml (P less than 0.01). Renin was markedly elevated. These changes were accompanied by marked and sustained clinical improvement and subjective well-being.

How seals avoid myocardial infarction when they should have got it.

The arterial oxygen tension of diving seals decreases to values as low as 1.33 kPa at the end of prolonged dives. In spite of this, cardiac function is unimpaired due to a profound reduction of myocardial oxygen demands: Heart rate is immediately reduced some 90%, left ventricular dP/dt(max) is reduced some 25%, and ventricular wall tension is slightly reduced. This reduction of myocardial workload even allows coronary blood flow to be reduced some 90% and a significant proportion of myocardial energy expenditure to be covered by anaerobic metabolism based on endogenous stores of glycogen. It is suggested that the myocardial ischaemic defence, as worked out by nature herself, in the diving seal has important implications for the treatment of acute myocardial ischaemia in man.

Sustained haemodynamic effects of enalapril in left ventricular failure.

Enalapril, a novel angiotensin converting enzyme inhibitor, was given orally to 12 patients with chronic heart failure (NYHA functional class III and VI) and cardiomegaly. Heart rate, systemic arterial blood pressure, pulmonary arterial pressure, right and left ventricular filling pressures and cardiac index were monitored during dose efficacy titration. The optimal dose averaged 17 mg given once-daily. All patients were recatheterized three months later. After stabilization of cardiac filling pressures, all patients had left ventricular filling pressures in excess of 18 mmHg. Enalapril increased cardiac index acutely by 34% but at 12 weeks follow-up, cardiac index was not different from control levels. Left ventricular filling pressure was reduced acutely by 36% and by 41% at three months. Heart rate, systemic arterial and right atrial pressures and plasma concentrations of aldosterone were reduced during the observation period. Renin was markedly elevated. These changes were accompanied by marked and sustained clinical improvement and subjective well-being.

Cardiac output and its distribution through capillaries and A-V shunts in diving seals.

Regional blood flow and cardiac output were determined by distribution of radioactive microspheres injected via catheter into the left ventricle during experimental diving and recovery in juvenile spotted seals (Phoca vitulina largha) and grey seals (Halichoerus grypus). Cardiac output was 9.7 L/min before diving, declined 90% during submersion and increased to 12.1 L/min after 40 s of recovery. Left ventricular myocardial perfusion declined from 179 +/- 24 (21) to 25 +/- 2 (6) ml/min . 100 g at 2 min submersion, and measured 23 +/- 3 (8) after 10 min of submersion. Cerebral cortical flow was reduced from a pre-dive value of 115 +/- 3 (15) to 40 +/- 5 (3) and 49 +/- 6 (3) at 2 and 5 min of diving, respectively, but increased to 253 +/- 14 (4) ml/min . 100 g at 10 min along with elevated PCO2 (84 torr) and lowered pH (7.10) in arterial blood. It remained at that level in recovery. Brain stem perfusion after 10 min submersion was still identical with control, but increased to 275% of control in recovery. Adrenal flow decreased to 34 and 27% of control at 2 and 5 min of diving, respectively. Recovery flow after 10 min of diving was 200% of control. Liver, kidney, fat, skin, and stomach were ischemic throughout the dive. Recovery flow increased slowly in these tissues. Skeletal muscle (M. psoas) was perfused at a low rate. (3 ml/min . 100 g) pre-dive and was ischemic during diving. Recovery muscle perfusion was variable at different sites (from 5 to 105 ml/min . 100 g). Pre-dive pulmonary capillary perfusion was 58 +/- 8 (9) ml/min . 100 g, decreased to 7 +/- 0 (3) ml/min . 100 g min of submersion, and had increased to 50% of pre-dive value after 40 s of recovery from a 10 min dive. Conclusions are: (1) previous information from implanted flow transducers was confirmed, (2) detailed data for discrete tissues elaborate the concept of selective redistribution of cardiac output in diving seals, (3) non-uniform reperfusion contributes to the maintenance of arterial pressure during recovery, and (4) substantial A-V shunting of cardiac output took place in the first 2-5 min of the dive, when total capillary/nutritive flow was low. Late in the dive, however, CO was routed through systemic capillaries mainly in the cerebral circulation and less than 15% through A-V shunts.

Haemodynamic and metabolic effects of timolol (Blocadren) on ischaemic myocardium.

The effects of timolol (2.5 mg i.v.) on coronary haemodynamics and myocardial metabolism were studied in 26 patients with angina pectoris. Cardiac venous flow (CVF) was measured by thermodilution technique. Blood was sampled for metabolic studies. Angina pectoris was induced by atrial pacing and the same heart rate was regained after timolol. Metabolic ischaemia was defined as reduction in myocardial lactate extraction ratio (MLE) by at least 50% and to a ratio below 0.15. The study was completed in 22 patients, 9 of whom fulfilled the metabolic criteria for ischaemia. This subgroup did not differ from the total group in any other respect than in lactate metabolism. Beta-adrenergic blockade reduced myocardial oxygen consumption (MVO2) and CVF significantly at rest, but MVO2, CVF, myocardial glucose uptake and MLE were unchanged during pacing despite a decrease in systolic aortic pressure, ejection time and reduced myocardial free fatty acid uptake. Conclusively, timolol did not reduce MVO2 and metabolic ischaemia during pacing-induced angina.

Myocardial blood flow and metabolism in the diving seal.

The adaptations of myocardial metabolism to diving asphyxia have been studied in 12 harbor seals (Phoca vitulina). Unanesthetized animals were submerged for periods of 10-16 min. Heart rate decreased from 135 to 12 beats/min. Myocardial blood flow decreased to an average of 10% of predive values and remained constant during the dive. The progressive reduction in arterial O2 content was associated with an increase in myocardial lactate and hydrogen ion production, but no change in glucose or free fatty acid extraction occurred. After restoration of breathing a reactive myocardial hyperemia and an immediate return to myocardial uptake of lactate were observed. Despite increased glycogenolytic activity throughout the dive, coronary flow distribution was fully controlled, and no evidence of ischemic dilatation of the left ventricle or S-T segment elevation in the electrocardiogram was observed. These adaptations to diving asphyxia in the seal myocardium permit a reduction of coronary blood flow comparable to that observed in the infarcted dog myocardium and therefore have relevance for therapeutic approaches to reduction of myocardial ischemic injury in humans.

Beneficial effects of vagal stimulation on the ischaemic myocardium during beta-receptor blockade.

The effect of vagal stimulation on the myocardial ischaemia produced by acute coronary occlusion during beta-receptor blockade has been examined. Epicardial ST-segment elevation, myocardial surface temperature and regional blood flow were determined 10 min after coronary occlusion in the dog. Coronary occlusion after beta-receptor blockade alone raised the average ST-segment from 0.5 +/- 0.3 to 3.1 +/- 0.5 mV (SEM) (p less than 0.001). Subsequent vagal stimulation with beta-receptor blockade, which reduced heart rate from 129 to 50 beats/min, mean arterial pressure from 123 to 78 mmHg, but increased cardiac output from 1164 to 1855 ml/min, resulted in marked reduction in ST-segment elevation to 0.3 +/- 0.2 mV which was not different from the control before occlusion. Epicardial temperature was markedly decreased in the ischaemic area following coronary occlusion. The temperature difference between central ischaemic and surrounding areas became smaller after beta-receptor blockade, and vanished during vagal stimulation. Vagal stimulation caused a 55% decrease of blood flow in all non-ischaemic regions. A smaller reduction took place in the border zone where flow values close to those of the non-ischaemic myocardium were obtained. In the central ischaemic area blood flow remained unchanged despite the reduction in arterial pressure. Thus, vagal stimulation resulted in decreased collateral resistance in the ischaemic area and a marked reduction of myocardial oxygen requirement of both non-ischaemic and border zone myocardium, additional to that obtained with beta receptor blockade. The provision of energy to the ischaemic myocardium is therefore very favourably balanced with its actual demand during vagal stimulation.