Myocardial damage in breast cancer patients treated with adjuvant radiotherapy: a prospective study.

PURPOSE: To look for early and late signs of cardiac side effects of postoperative radiotherapy in patients with left-sided breast cancer. METHODS AND MATERIALS: Seventeen left-sided primary (Stage I-III) breast cancer patients considered eligible were recruited. Their computer tomography-based dose planning showed a part of the heart's left ventricle irradiated with at least 85-95% of the total dose. Twelve patients were examined both before treatment and an average of 13 months later, at a first follow-up. In partially mastectomized patients tangential opposed photon fields were used to the breast tissue, while in patients with modified radical mastectomy electrons were given to the thorax. Echocardiography and a bicycle ergometry stress test with myocardial perfusion scintigraphy were carried out before and after radiotherapy to assess if any myocardial damage could be detected. RESULTS: Six of the 12 patients exhibited new fixed scintigraphic defects after radiotherapy indicating regional hypoperfusion. Four of them received treatment only to the breast after breast-conserving surgery. The localization of the defects corresponded well with the irradiated volume of the left ventricle. No deterioration in left ventricular systolic or diastolic function could be detected by echocardiography. CONCLUSIONS: In this study half of the patients exhibited new scintigraphic defects that indicate radiation-induced myocardial damage, probably affecting the microcirculation. There were no changes on electrocardiography or any deterioration of the left ventricular function at this stage. Long-term follow-up is necessary to assess whether this finding is a prognostic sign for developing radiation-induced coronary artery disease.

Morbidity of ischemic heart disease in early breast cancer 15-20 years after adjuvant radiotherapy.

PURPOSE: To assess the cardiac side effects, primarily the occurrence of ischemic heart disease in symptom-free patients with early breast cancer treated with radiotherapy. METHODS AND MATERIALS: Thirty-seven survivors of a former randomized study of early breast cancer were examined. Twenty patients irradiated pre- or postoperatively for left sided disease (study group patients) were compared with 17 controls who were either treated for right sided disease, or were nonirradiated patients. Radiotherapy was randomized in the original study; either tangential field 60Co, or electron-therapy was delivered. Echocardiography and bicycle ergometry stress test with 99mTc SestaMIBI myocardial perfusion scintigraphy were carried out and the patients' major risk factors for ischemic heart disease were also listed. RESULTS: Our results showed a significant difference between the scintigraphic findings of the two groups. Five of the 20 study group patients (25%), while none of the 17 controls exhibited some kind of significant defects on scintigraphy, indicating ischemic heart disease (p < 0.05). No deterioration in left ventricular systolic and/or diastolic function could be detected by echocardiography. CONCLUSION: Radiotherapy for left sided breast cancer with the mentioned treatment technique may present as an independent risk factor in the long-term development of ischemic heart disease, while left ventricular dysfunction could not be related to the previous irradiation. We emphasize the need to optimize adjuvant radiotherapy for early breast cancer by considering the dose both to the heart as well as the cancer.

Mononitrates as monotherapy in the prophylactic treatment of angina pectoris.

This article reviews the results of double-blind comparative studies on the therapeutic use of isosorbide 5-mononitrate as monotherapy in the prophylaxis of angina pectoris. Isosorbide 5-mononitrate appears at least as effective as the same dosage of isosorbide dinitrate and is probably superior to the calcium antagonists. Recent data have shown that isosorbide 5-mononitrate in a controlled-release formulation given once daily has a significantly better antianginal effect than placebo without inducing the development of tolerance.

ST-segment depression on ambulatory electrocardiography in the early in-hospital period after acute myocardial infarction predicts early and late mortality: a short-term and a 3-year follow-up study.

A surveillance study was conducted to determine the in-hospital and long-term prognostic value of ST-segment depression assessed by ambulatory electrocardiographic monitoring (AEM) during the early in-hospital period after acute myocardial infarction (AMI). ST-segment depression (STD) was determined by computer analysis of 24-h ECG tapes as a horizontal or downsloping change in ST level by > 0.1 mV from the reference base line. The ST level was measured 80 ms after the J point of all normally conducted complexes for > or = 1 min. All computer-detected ST events were verified by one trained reader. Tapes corresponding to 74 patients were analyzed. In addition, 23 tapes corresponding to age- and gender-matched controls were also analyzed. Patients were divided into two groups: 22 patients (30%) showed STD (Group A), and 52 patients (70%) had no episode of STD (Group B). Among controls, 1 person (4%) showed STD. During the early follow-up period (14 +/- 11 days after hospital admission), cardiac events occurred in 11 patients [7 (32%) in Group A and 4(8%) in Group B, p < 0.01], including 6 cardiac death [5 (23%) in Group A and 1 (2%) in Group B, p < 0.01], 3 acute coronary artery bypass surgeries [2 (9%) in Group A and 1 (2%) in Group B, p = NS], and 2 nonfatal myocardial infractions (both in Group A, p = NS). During a mean follow-up period of 3 years (36 +/- 15 months), 18 patients died [10 (45%) in Group A and 8 (15%) in Group B, p = 0.01]. Eleven deaths were sudden [7 (32%) in Group A and 4 (8%) in Group B, p < 0.01]. Eighteen AMI occurred [11 (50%) in Group A and 7 (13%) in Group B, p < 0.005]. Twenty patients underwent revascularization procedures [7 (32%) in Group A and 13 (25%) in Group B, p = NS].(ABSTRACT TRUNCATED AT 250 WORDS)

The use of invasive techniques to study circulatory effects of nitrates.

The hemodynamic effects of NTG are easily studied with the use of invasive techniques. This article presents and discusses the most commonly used parameters obtained from cardiac catheterization and angiography to describe the effects of nitrates on the central circulation and the left ventricular function.

Left ventricular pump function in effort angina. Influence of nitroglycerin, propranolol, verapamil, and coronary bypass surgery.

Patients with severe effort angina were studied hemodynamically and left ventricular function curves were obtained during successively increasing myocardial ischemia provoked by exercise. The mean left ventricular function curve of 57 patients showed a slow increase in stroke work index with increasing left ventricular end-diastolic pressure at the beginning of exercise and stroke work index reached a maximum value of 0.79 (+/- 0.21) J/beat/m2 BSA at a left ventricular end diastolic pressure 30 (+/- 7) mm Hg. Despite a continuous increase in left ventricular end-diastolic pressure to 37 (+/- 6) mm Hg at the breaking point, stroke work index fell to its lowest value (0.64 +/- 0.21) J/beat/m2 BSA. A repeated exercise 20 min after the first in 10 patients did not influence the exercise tolerance or the left ventricular function curve. Although all the drugs nitroglycerin, propranolol and verapamil significantly increased the exercise tolerance none of the drugs enabled the patients to reach a significantly higher stroke work index. Only after nitroglycerin was there a significant increase (p greater than 0.05) of left ventricular power. After coronary bypass surgery with successful revascularization, however, there was a marked increase of both stroke work index and left ventricular power during exercise. Thus the increased exercise tolerance after surgery was accompanied by an increased left ventricular work and power but after medication no such effect on stroke work index and left ventricular power was seen. It is therefore suggested that the increased exercise tolerance after the anti-anginal drugs studied is a result of their different mechanisms of unloading the left ventricle.

Central haemodynamics in the immediate postoperative period after aortic valve replacement.

Twelve patients with aortic valve lesions were studied haemodynamically before operation and on the three consecutive days after uncomplicated aortic valve replacement with a Björk-Shiley tilting disc valve prosthesis. Five patients had pure aortic stenosis, 4 aortic insufficiency and 3 had combined lesions. Cardiac output at rest, which was within normal limits before operation, was unchanged on the first postoperative day, but showed a tendency to increase on the two following days. Heart rate was markedly increased postoperatively with a corresponding decrease in stroke volume. Arteriovenous oxygen difference was slightly higher postoperatively, indicating a more hypokinetic circulation after surgery. Right atrial mean pressure, which was normal preoperatively, increased in average 3 mmHg postoperatively, whereas left atrial mean pressure, which was pathologically elevated in most patients before operation, showed a marked decrease after operation with a corresponding decrease in pulmonary artery pressure. No significant change in radial artery pressure was observed. Pulmonary and systemic vascular resistance did not change significantly after surgery. The causes of tachycardia, decreased left atrial pressure and hypokinetic circulation after operation are discussed. It is suggested that, in spite of a positive fluid and blood balance, a relative hypovolaemia exists with insufficient blood volume in the left atrium, leading to diminished filling of the low-compliant left ventricle.

Effect of intravenous verapamil on exercise tolerance and left ventricular function in patients with severe exertional angina pectoris.

The hemodynamic effects of 0.1 mg/kg verapamil given intravenously to 7 patients with angina pectoris were studied at rest and during exercise in the supine position. Cardiac output was measured with the thermodilution technique, which permitted measurements every 30 sec during exercise. Maximal exercise tolerance increased significantly after verapamil. Verapamil had no effect on heart rate at rest, but significantly increased it at the end of the exercise. Left ventricular systolic pressure was reduced by verapamil at rest and during submaximal exercise. Left ventricular end-diastolic pressure was not influenced by verapamil at rest, but was significantly lowered during submaximal exercise. Stroke work index and left ventricular power index were not influenced by verapamil. Rate pressure product was lowered by verapamil during submaximal exercise but had a tendency to be increased at the breaking point. Verapamil had no negative inotropic effect as judged from the left ventricular function curve. It is suggested that the beneficial effect of verapamil relates mainly to a reduction of left ventricular pre- and after-load. The slightly higher rate pressure product after verapamil may also suggest a slight improvement of myocardial perfusion.

The effect of repeated supine exercise on exercise tolerance and left ventricular pump function in patients with angina pectoris.

The reproducibility of symptoms, exercise tolerance and haemodynamic variables describing left ventricular pump function have been studied at rest and during repeated supine exercise in ten patients with severe angina pectoris. Two exercise periods were performed about 20 min apart and the breaking point was in all cases determined by angina pectoris. The average working capacity was 22.5 W in both exercise periods. Duration of work, time to onset of angina and pain level at breaking point were not different in the two periods. There were no significant differences at rest nor during exercise for oxygen uptake, arterio-venous oxygen difference, heart rate, cardiac output, stroke volume, left ventricular systolic and end-diastolic pressure, pulmonary artery mean pressure, right atrial mean pressure, stroke work index or left ventricular work. Pressure-time index was significantly (P less than 0.01) higher in the second rest period but systolic pressure heart rate product was not significantly different. The high reproducibility with very small variations of the variables studied should permit the use of this protocol to study the acute haemodynamic effects of pharmacological interventions at rest and during exercise in patients with severe effort-induced angina pectoris.

Effect of physical exercise on internal carotid artery blood flow after arterial reconstruction.

The effect of physical exercise on internal carotid artery (ICA) blood flow in conscious man was studied with the aid of electromagnetic flowmetry. A flow probe was implanted on the ICA in 25 patients after reconstruction of the artery. ICA mean blood flow and brachial artery mean blood pressure were continuously monitored in supine (25 patients) and sitting (24 patients) position at rest, during 5-6 minutes exercise on a bicycle ergometer and at rest after exercise. Arterial carbon dioxide tension (PaCO2) was studied in 6/25 work tests in supine and 7/24 in sitting position. Cardiac output was measured at rest and during exercise in 10/25 patients in supine and 8/24 patients in sitting position. In the supine group, ICA flow increased significantly within 1 minute and reached a maximal flow 15% above control flow within 2 minutes after the onset of exercise. The ICA flow then gradually declined, but remained almost significantly elevated, 7.5% above control, on termination of exercise. At rest, after exercise, the ICA flow decreased almost significantly to a level of 5% below the control flow within 5 minutes. There was a significant PaCO2 increase of 2.6 mmHg during exercise and a highly significant increase (72%) in cardiac output during exercise. The ICA flow at rest, before exercise, was about 15% lower in the sitting group than in the supine group. It increased in average 11.5% with 2 minutes of exercise and then gradually diminished. At rest, after exercise, ICA flow decreased further to a level of 8% below control flow within 5 minutes. PaCO2 increased significantly in average 1.6 mmHg during exercise. Cardiac output increased highly significantly (85%) during exercise. The ICA flow changes obtained during exercise in the present study indicate the presence of a regulatory mechanism counteracting the increasing perfusion pressure, but it is unable to compensate the decreased perfusion pressure when the body position was altered from supine to sitting. The cerebral vascular bed in the present patient material seems to operate above and below the lower limit of its pressure range for an adequate autoregulation.

Left ventricular pump function before and after aortocoronary bypass surgery.

Ten patients with severe effort angina and with left ventricular dysfunction during exercise before operation underwent haemodynamic and angiographic studies in average 20 months after coronary artery bypass surgery. Five patients (50%) were completely asymptomatic after operation(group I). The other five (group II) were still limited physically because of anginal pain, although two were much improved. Pre-operatively there was no significant difference in the severity of the disease, as judged from case histories, work tests and haemodynamic and angiographic findings between the two groups. The working capacity of the patients in group II was not increased significantly post-operatively. Their coronary arteriograms revealed unsatisfactory surgical results. In two patients, one significantly stenosed vessel was not bypassed because of poor run-off. In the other three patients, one graft was closed. Left ventricular function curves showed no significant improvement of left ventricular pump function. In group I, working capacity increased significantly, all stenoses of major coronary vessels were bypassed and all grafts were patent. Left ventricular function showed an almost normal response during exercise. These findings suggest that left ventricular dysfunction due to ischaemia can be significantly improved by coronary bypass and that there is a good correlation between clinical, haemodynamic and angiographic findings.

Left ventricular pump function in effort angina.

The successive deterioration of left ventricular pump function during exercise-induced angina pectoris was studied in 20 candidates for aortocoronary bypass surgery. Left ventricular stroke work and power were calculated from continuous left ventricular pressure recordings and repeated measurements of cardiac output every 30 sec using the thermodilution technique. The average left ventricular enddiastolic pressure (LVEDP) increased continuously during exercise whereas stroke work index (SWI) did so only in the beginning of the exercise period up to a maximum value and then fell towards the end of exercise. The onset of angina occurred at an average LVEDP of 34 mm Hg when SWI had already started to fall in most patients. During exercise all patients had markedly lower SWI than normals. Patients with high coronary arteriographic score and patients with a previous myocardial infarction had significantly lower SWI during exercise than those with low score or those without a previous infarct. At rest there were no differences between these groups which emphasises the importance of haemodynamic measurements under stress conditions in patients with ischaemic heart disease.

Assessment of atrial contribution to left ventricular filling during cold pressor test by M-mode echocardiography in patients with coronary artery disease.

To determine whether temporarily increased afterload causes changes in left ventricular (LV) diastolic properties, we examined 19 patients with coronary artery disease (CAD) and 14 healthy subjects by M-mode echocardiography during immersion of the left hand in ice water. The M-mode echocardiograms were digitized to assess the percentage of atrial contribution (%AC) to LV filling as a marker of diastolic properties. Six patients and 5 controls had to be excluded owing to inability to clearly define the endocardium in the left ventricle throughout the entire heart cycle. In the control situation, the %AC did not differ significantly between the two groups. During the cold pressor test, the mean %AC at peak systolic and peak diastolic pressures was significantly higher in the CAD group than in the control group (p less than 0.05). Thus, by using M-mode echocardiography during the cold pressor test it is possible to document an increased atrial contribution to LV filling in patients with CAD. It is suggested that the mechanism is increased myocardial stiffness evoked by ischaemia with a resultant increased role of atrial contraction.

Effects of exercise on the displacement of the atrioventricular plane in patients with coronary artery disease. A new echocardiographic method of detecting reversible myocardial ischaemia.

The effect of exercise on the displacement of the atrioventricular (AV) plane was studied by echocardiography (echo) in 48 patients with stable angina pectoris without prior myocardial infarction and 20 age-matched healthy subjects. Echo was performed at rest, immediately after and 10 and 30 min after the test. The patients also underwent thallium stress scintigraphy and coronary angiography. From the apical four- and two-chamber views, the atrioventricular plane displacement (AVPD) during the cardiac cycle was recorded at four sites corresponding to the septal, anterior, lateral and posterior walls of the left ventricle and a mean value was calculated (AV-mean). The healthy subjects and patients had almost the same AVPD at all the sites at rest (AV-mean of 14.5 and 14.2 mm respectively). Immediately post-exercise the healthy subjects showed a significant (P less than 0.001) and equally distributed increase in the AVPD at all the sites with an AV-mean value of 19.2 mm. In most of the patients with angiographically confirmed coronary artery disease (CAD), there was a reversible decrease of AVPD (greater than or equal to 3 mm) at one or more of the AV plane sites. The overall sensitivity and specificity were 80% and 100% respectively in identifying CAD patients. The changes correlated well with the reversible ischaemic changes on the thallium scan (sensitivity, 88%, and specificity, 83%). A generalized exercise-induced decrease in AVPD at all the recorded sites had a high specificity (91%) in detecting patients with three-vessel disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Sympathoadrenal responses to bronchoconstriction in asthma: an invasive and kinetic study of plasma catecholamines.

1. Bronchoconstriction does not seem to be a stimulus for sympathoadrenal activation, as judged by venous plasma concentrations of noradrenaline, adrenaline or neuropeptide Y-like immunoreactivity. However, venous measurements have methodological drawbacks. In the present study arterial and mixed venous (pulmonary arterial) levels of these variables were determined before and after histamine-induced bronchoconstriction in non-medicated asthmatic subjects. In addition, noradrenaline kinetics in plasma (isotope dilution) and the pulmonary overflows of noradrenaline and neuropeptide Y-like immunoreactivity were determined. 2. Histamine inhalation induced bronchoconstriction; forced expiratory volume in ls decreased by 38.7% +/- 4.1% (SE) and arterial PO2 by 3.0 +/- 0.9 kPa. This acute bronchoconstriction induced significant elevations of arterial and mixed venous plasma noradrenaline from < or = 1.18 nmol/l to > or = 1.40 nmol/l. The clearance of NA from plasma increased marginally. Thus, the arterial plasma NA response was due to increased spillover of noradrenaline to plasma (from 1.80 +/- 0.18 to 2.52 +/- 0.36 mmol min-1/m2 at maximal bronchoconstriction, with a subsequent further increase). There were no elevations of adrenaline or neuropeptide Y-like immunoreactivity in arterial plasma. 3. No sympathetic activation could be demonstrated in the lungs (pulmonary noradrenaline or neuropeptide Y-like immunoreactivity overflow), and no alterations in pulmonary vascular resistance or cardiac output were observed. Neither arterial nor mixed venous plasma concentrations of adrenaline were influenced by bronchoconstriction. 4. Acute bronchoconstriction thus leads to peripheral sympathetic activation (possibly due to the increased work of breathing) which does not involve the lungs.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of a modified acetylene rebreathing method for the determination of cardiac output.

In order to evaluate a computerized modified acetylene rebreathing method for the determination of cardiac output, 15 healthy subjects were studied at different levels of their maximal oxygen uptake (VO2max). Submaximal exercise was performed on a cycle ergometer and maximal exercise on a treadmill. Oxygen uptake, heart rate, and cardiac output (acetylene method) were determined in all test situations. In seven subjects simultaneous determinations of cardiac output were made by a modified acetylene rebreathing method (QA) and a dye dilution method (QD). Furthermore, a new resting rebreathing technique was used. The methodological error for QA (means of double samples) was 0.37 litre min-1 (2.8%) in the same individual at 150 W. The corresponding values between individuals were 0.71 (rest), 0.41 (50 W), 0.69 (150 W), and 0.40 litre min-1 (VO2max). Thus the methodological error of the modified acetylene method was very low. There was a significant difference (P less than 0.01), however, between the acetylene method and the dye dilution method, which showed a lower value for QA at all levels. This was probably due to the long response time of the mass spectrometer combined with anatomical and physiological arteriovenous shunt effects in the lungs during exercise. When these factors were considered the correcting formula was: QAc = QA + 0.005 X Q2A. There was no significant difference between the corrected cardiac output values (QAc), and the corresponding QD values. In conclusion, this modified acetylene rebreathing method is a very useful non-invasive method for measuring cardiac output at rest as well as during heavy exercise.

ST depression and left ventricular haemodynamics during exercise in patients with angina pectoris.

The mechanism of ischaemic ST depression and the cause of its low sensitivity to coronary artery stenosis are not well understood. Of 30 patients with severe stable effort angina, 19 (63%) showed ischaemic ST depressions after exercise (the STAE group) and 11 did not. The highest load during the symptom-limited exercise test and the heart rate on that load did not differ between the two groups. The clinical characteristics and angiographic findings were also similar, but the findings at heart catheterization differed during exercise (in supine). Although the load was similar, the stroke index was significantly lower (38 vs. 53 ml/m2 BSA) and the left ventricular end-diastolic pressure rose to a significantly higher value in the STAE group (40 vs. 32 mmHg). When STAE occurred, they were exclusively or concomitantly present in chest lead 5. These findings suggest that ischaemic STAE may not reflect regional ischaemia but the consequent left ventricular dysfunction. The mechanism may, for example, be that a sufficiently elevated left ventricular diastolic pressure causes a global subendocardial ischaemia.

Does post-exercise ST depression reflect local ischemia or some global effect in the left ventricle?

As exercise-induced ST depressions are most frequent and marked in lead V5 independent of which single coronary artery is obstructed, some other mechanisms of ST depressions than local ischemia should be searched for. Left ventricular hemodynamics during exercise was studied in two groups of patients with severe effort angina, 19 with and 12 without ST depression after exercise (STAE). During supine exercise until angina, stroke index became significantly lower (37 vs. 52 ml/m2) and left ventricular end-diastolic pressure (LVEDP) significantly higher (40 vs. 30 mmHg) in the STAE group. The best discriminator was the early diastolic pressure (LVeDP) (22 vs. 11 mmHg), which is interpreted as a sign of a more ischemic ventricle in the STAE group. The sum of STAE in all leads is correlated to LVeDP but not to LVEDP during exercise. The link between the significant ischemia in various locations and STAE appearing most frequently and markedly in V5 seems to be some global mechanism as the occurrence of STAE and the height of the R wave were positively correlated in the various leads. As STAE in coronary heart disease shows similar configuration and distribution as in aortic valvular stenosis and digoxin medication of healthy subjects, a possible link could be the compensatory increase in contractility in non-ischemic parts of the ventricle.

Cardiovascular and renal responses to acute cold exposure in water-loaded man.

Changes in oxygen uptake, cardiac output, heart rate, stroke volume, central blood volume, arteriovenous oxygen difference, aortic, pulmonary arterial, and right atrial blood pressure, systemic vascular resistance, hematocrit, circulating plasma volume, urine flow, fractional sodium excretion, and free water clearance were studied in eight healthy volunteers in stable water diuresis, exposed to cold by means of air at +15 degrees C and at a speed of 0.5 m/sec. A decrease in circulating plasma volume and systemic vascular resistance was found during cold stress. Mean aortic blood pressure, sodium excretion, cardiac output, oxygen uptake, arteriovenous oxygen difference, and hematocrit increased. No changes in urine flow or in clearance of free water could be demonstrated. Heart rate, stroke volume, and central blood volume showed significant increases in cold. The results are interpreted to suggest that exposure to cold raises the arterial blood pressure by an increase in cardiac output, thereby increasing capillary hydrostatic pressure in certain vascular areas, including the renal vascular bed. This negatively affects capillary reabsorption processes in the kidney, causing a reduction in tubular sodium reabsorption, thus giving rise to a natriuresis. In other areas it seems to cause a shift of fluid towards the intersitial space.

Detection of radiation-induced myocardial damage by technetium-99m sestamibi scintigraphy.

A prospective study was initiated to assess the side-effects of postoperative adjuvant radiotherapy in patients with left-sided early breast cancer. Twelve patients with early breast cancer were examined before and a year after radiotherapy. Echocardiography, ECG and bicycle ergometry stress test with technetium-99m sestamibi myocardial perfusion scintigraphic were carried out to assess changes in regional myocardial blood flow. Six of the 12 patients had new fixed scintigraphic defects after radiotherapy (as compared with the preradiation examination). The localization of the defects corresponded well with the irradiated volume of the left ventricle. These defects were probably due to microvascular damage to the myocardium. Neither ECG changes nor left ventricular segmental wall motion abnormalities could be detected by echocardiography. To our knowledge this study is the first to show that radiation-induced micro-vascular damage to the myocardium may be detected by perfusion scintigraphy. This may limit the use of scintigraphy in diagnosing coronary artery disease in patients treated with thoracic radiotherapy. Long-term follow-up is necessary to assess whether the presence of microvascular damage is a prognostic sign for the development of radiation-induced coronary artery disease.