Comorbidities, risk factors and outcomes in patients with heart failure and an ejection fraction of more than or equal to 40% in primary care- and hospital care-based outpatient clinics.

OBJECTIVE: The aim of this study is to describe patients with heart failure and an ejection fraction (EF) of more than or equal to 40%, managed in both Primary- and Hospital based outpatient clinics separately with their prognosis, comorbidities and risk factors. Further to compare the heart failure medication in the two groups. DESIGN: We used the prospective Swedish Heart Failure Registry to include 9654 out-patients who had HF and EF ≥40%, 1802 patients were registered in primary care and 7852 in hospital care. Descriptive statistical tests were used to analyze base line characteristics in the two groups and multivariate logistic regression analysis to assess mortality rate in the groups separately. SETTING: The prospective Swedish Heart Failure Registry. SUBJECTS: Patients with heart failure and an ejection fraction (EF) of more than or equal to 40%. MAIN OUTCOME MEASURES: Comorbidities, risk factors and mortality. RESULTS: Mean-age was 77.5 (primary care) and 70.3 years (hospital care) p < 0.0001, 46.7 vs. 36.3% women respectively (p < 0.0001) and EF ≥50% 26.1 vs. 13.4% (p < 0.0001). Co-morbidities were common in both groups (97.2% vs. 92.3%), the primary care group having more atrial fibrillation, hypertension, ischemic heart disease and COPD. According to the multivariate logistic regression analysis smoking, COPD and diabetes were the most important independent risk factors in the primary care group and valvular disease in the hospital care group. All-cause mortality during mean follow-up of almost 4 years was 31.5% in primary care and 27.8% in hospital care. One year-mortality rates were 7.8%, and 7.0% respectively. CONCLUSION: Any co-morbidity was noted in 97% of the HF-patients with an EF of more than or equal to 40% managed at primary care based out-patient clinics and these patients had partly other independent risk factors than those patients managed in hospital care based outpatients clinics. Our results indicate that more attention should be payed to manage COPD in the primary care group. KEY POINTS 97% of heart failure patients with an ejection fraction of more than or equal to 40% managed at primary care based out-patient clinics had any comorbidity. Patients in primary care had partly other independent risk factors than those in hospital care. All-cause mortality during mean follow-up of almost 4 years was higher in primary care compared to hospital care. In matched HF-patients RAS-antagonists, beta-blockers as well as the combination of the two drugs were more seldom prescribed when managed in primary care compared with hospital care.

Sex-related differences among young adults with heart failure in Sweden.

BACKGROUND: Differences between the sexes among the non-elderly with heart failure (HF) have been insufficiently evaluated. This study aims to investigate sex-related differences in early-onset HF. METHODS: Patients aged 18 to 54 years who were registered from 2003 to 2014 in the Swedish Heart Failure Register were included. Each patient was matched with two controls from the Swedish Total Population Register. Data on comorbidities and outcomes were obtained through the National Patient Register and Cause of Death Register. RESULTS: We identified 3752 patients and 7425 controls. Of the patients, 971 (25.9%) were women and 2781 (74.1%) were men with a mean (standard deviation) age of 44.9 (8.4) and 46.4 (7.3) years, respectively. Men had more hypertension and ischemic heart disease, whereas women had more congenital heart disease and obesity. During the median follow-up of 4.87 years, 26.5 and 24.7 per 1000 person-years male and female patients died, compared with 3.61 and 2.01 per 1000 person-years male and female controls, respectively. The adjusted hazard ratios for all-cause mortality, compared with controls, were 4.77 (3.78-6.01) in men and 7.84 (4.85-12.7) in women (p for sex difference = 0.11). When HF was diagnosed at 30, 35, 40, and 45 years, women and men lost up to 24.6 and 24.2, 24.4 and 20.9, 20.5 and 18.3, and 20.7 and 16.5 years of life, respectively. CONCLUSION: Long-term mortality was similar between the sexes. Women lost more years of life than men.

Cardiac repolarization and its relation to ventricular geometry and rate in reverse remodelling during antihypertensive therapy with irbesartan or atenolol: results from the SILVHIA study.

Hypertensive left ventricular (LV) hypertrophy is associated with a substantial risk for malignant arrhythmias and sudden death. According to recent results, antihypertensive therapy with the angiotensin II type 1 receptor blocker irbesartan reverses both structural and electrical remodelling. However, the relation between the LV geometric pattern (concentric vs eccentric) and electrical reverse remodelling has not been characterized, neither has the relation between repolarization and rate (QT/RR and JT/RR relation), which presumably reflects the propensity for bradycardia-dependent ventricular arrhythmia. In this study, repeat echocardiographic and electrocardiographic measurements were performed in hypertensive patients with LV hypertrophy, randomized to double-blind therapy with irbesartan (n = 44) or the beta(1)-adrenoceptor blocker atenolol (n = 48) for 48 weeks; 53 patients had concentric and 39 eccentric LV hypertrophy. In addition, 37 matched hypertensive subjects without LV hypertrophy and no current therapy served as controls. Irbesartan induced structural and electrophysiological reverse remodelling, independent of LV geometry. In contrast, atenolol had similar beneficial effect only in patients with concentric LV hypertrophy, while the response in those with eccentric hypertrophy was unfavourable with both prolonged repolarization time and an increased QT/RR slope (suggesting reverse-use dependence). In conclusion, there is a significant geometry-related difference in the reverse remodelling processes induced by irbesartan and atenolol. Echocardiographic characterization of the geometry in hypertension-induced LV hypertrophy might become an important step in the selection of optimal antihypertensive therapy.

Predicting readmissions and cardiovascular events in heart failure patients.

AIMS: To analyse measures of clinical data, functional capacity, left ventricular function and neurohormonal activation for the ability to predict mortality and morbidity in patients after a hospitalisation for heart failure. METHODS: In a prospective study, patients 60 years or above with systolic heart failure NYHA II-IV were followed for at least 18 months. At study start, a physical examination, echocardiography, blood samples and measurements of quality of life (QoL) by Nottingham Health Profile were obtained. Data on mortality and readmission rates were collected. RESULTS: 208 patients, 58% men, with a mean age of 76 years, and an ejection fraction of 0.34 were included and followed for a mean of 1,122 days. In all, 74 (36%) patients died and 171 (82%) were readmitted. By univariate analysis, readmissions were predicted by poor QoL (169 +/- 118 vs. 83 +/- 100, p < 0.001), age, creatinine, haemoglobin (p < 0.01 all) and diabetes (p < 0.1). By multivariate analyses, QoL at study start was the only independent predictor of readmissions (chi(2) = 25.2, p < 0. 001). Mortality was univariately associated with QoL (183 +/- 117 vs. 142 +/- 115, p < 0.05) and in multivariate analyses to traditional variables: age, male gender, systolic function, BNP and serum creatinine (chi(2) = 48.9, p < 0.001). CONCLUSIONS: Measurements representing different aspects of the heart failure syndrome can easily be obtained to stratify long-term risks of mortality and morbidity in hospitalised heart failure patients. Poor QoL was a univariate predictor for mortality and a strong multivariate predictor for the important outcome of readmission, pointing to the need for a simple assessment of QoL.

Regression of left ventricular hypertrophy in human hypertension with irbesartan.

BACKGROUND: The Swedish irbesartan left ventricular hypertrophy investigation versus atenolol (SILVHIA). OBJECTIVE: Angiotensin II induces myocardial hypertrophy. We hypothesized that blockade of angiotensin II subtype 1 (AT1) receptors by the AT1-receptor antagonist irbesartan would reduce left ventricular mass (as measured by echocardiography) more than conventional treatment with a beta blocker. DESIGN AND METHODS: This double-blind study randomized 115 hypertensive men and women with left ventricular hypertrophy to receive either irbesartan 150 mg q.d. or atenolol 50 mg q.d. for 48 weeks. If diastolic blood pressure remained above 90 mmHg, doses were doubled, and additional medications (hydrochlorothiazide and felodipine) were prescribed as needed. Echocardiography was performed at weeks 0, 12, 24 and 48. RESULTS: Baseline mean blood pressure was 162/ 104 mmHg, and mean left ventricular mass index was 157 g/m2 for men and 133 g/m2 for women. Systolic and diastolic blood pressure reductions were similar in both treatment groups. Both irbesartan (P < 0.001) and atenolol (P< 0.001) progressively reduced left ventricular mass index, e.g. by 26 and 14 g/m2 (16 and 9%), respectively, at week 48, with a greater reduction in the irbesartan group (P = 0.024). The proportion of patients who attained a normalized left ventricular mass (i.e. < or = 131 g/m2 for men and < or = 100 g/m2 for women) tended to be greater with irbesartan (47 versus 32%, P = 0.108). CONCLUSIONS: Left ventricular mass was reduced more in the irbesartan group than in the atenolol group. These results suggest that blocking the action of angiotensin II at AT1-receptors may be an important mechanism, beyond that of lowering blood pressure, in the regulation of left ventricular mass and geometry in patients with hypertension.

Results of atrioventricular synchronous pacing with optimized delay in patients with severe congestive heart failure.

To verify that atrioventricular (AV) synchronous pacing (DDD) with short AV delay improves the condition of patients with severe congestive heart failure, we implanted DDD pacemakers in 10 patients with severe heart failure (New York Heart Association [NYHA] class III to IV). One day after pacemaker implantation, the AV delay was optimized by Doppler echocardiographic measurements over the aortic outflow tract. Patients were evaluated regarding NYHA class, stroke volume, cardiac output, ejection fraction, and quality of life at 1, 3, and 6 months after pacemaker implantation. Although the optimized AV delay was associated with short-term improvement in stroke volume and cardiac output (baseline stroke volume = 22 +/- 7 ml, day 1 = 28 +/- 12 ml; p = 0.03: baseline cardiac output = 1.9 +/- 0.6 L/min, day 1 = 2.2 +/- 1.1 L/min; p = 0.10), the mean stroke volume, cardiac output, NYHA class, and ejection fraction did not change significantly after 1, 3, and 6 months of pacing compared with baseline values. Three patients improved in NYHA class during the follow-up. A consistent improvement in stroke volume, cardiac output, NYHA class, and ejection fraction was observed in only 1 patient. In conclusion, we found no beneficial effects of AV-synchronous pacing with optimized AV delay in patients with severe heart failure.

Attenuation of left ventricular dilatation after acute myocardial infarction by early initiation of enalapril therapy. CONSENSUS II Multi-Echo Study Group.

This trial investigated the effect of enalapril, administered early, on left ventricular (LV) volumes after myocardial infarction. Four hundred twenty-eight patients included in the Cooperative New Scandinavian Enalapril Survival Study (CONSENSUS II) were examined with echocardiography within 5 days, at 1 month and at 6 months after myocardial infarction. Enalaprilat (1 mg) or placebo infusion was initiated within 24 hours after infarction, followed by oral treatment to a target dose of 20 mg/day. A significant attenuation of LV dilatation was noted at 1 month in patients treated with enalapril compared with those receiving placebo. Changes in LV end-diastolic volume indexes during the first month were (mean +/- SEM) 5.7 +/- 1.0 ml/m2 for the placebo group and 1.9 +/- 0.8 ml/m2 for the enalapril group (p < 0.02). Changes in LV end-systolic volume indexes were 3.1 +/- 0.8 and 0.5 +/- 0.6 ml/m2, respectively (p < 0.02). The between-group difference was most marked in patients with anterior wall infarction (p < 0.005). Volume changes beyond the first month were similar in both groups but the differences observed at 1 month were maintained. The larger volumes in the placebo versus enalapril group were significant or borderline significant at 1 and 6 months. Thus, enalapril treatment initiated early after myocardial infarction and continued for 6 months can attenuate LV dilatation during the first month resulting in smaller LV volumes after 1 and 6 months.

Epidemiology of heart failure in Sweden--a national survey.

BACKGROUND: In Sweden heart failure is the most frequent discharge diagnosis within internal medicine. The prevalence of heart failure seems to be increasing, mainly due to an ageing population, but also because of improved survival in patients with cardiovascular diseases. AIM: To describe the epidemiology of heart failure in Sweden from a perspective based on demographic and health care data. METHODS: The national registers in Sweden provide detailed information on health care consumption in relation to different diagnoses. Pharmaceutical sales are also registered. There are national epidemiological reports, reports on health care utilization and on health economics concerning heart failure patients. RESULTS: There has been structural changes in the Swedish health care system due to financial restraints in the health care budget. Aiming at reducing hospital costs, the total amount of hospital beds has been cut down markedly during the last decade. The number of heart failure patients and the number of hospital stays have increased during the same period. Hospital stays have become shorter. The number of patients and hospital stays more than double when heart failure as both primary and secondary discharge diagnoses are included. CONCLUSION: The available national registers provide a good opportunity to study epidemiology of heart failure in Sweden. The number of hospital beds has decreased markedly within the last decade due to changes in the Swedish health care system. Nevertheless, there has been an increase in the number of patients discharged with heart failure from the hospitals, suggesting an increase in prevalence.

Doppler tissue imaging in congestive heart failure patients due to diastolic or systolic dysfunction: a comparison with Doppler echocardiography and the atrio-ventricular plane displacement technique.

BACKGROUND: Doppler tissue imaging (DTI) is an echocardiographic technique by which regional contractility, relaxation properties and time intervals are obtained easily. DTI has been reported to be relatively pre-load independent and could, in comparison with the commonly used mitral pulse wave Doppler (MPWD) method, be of clinical interest for identification of patients with diastolic dysfunction. The atrio-ventricular plane displacement (AVPD) method is an established technique to assess left ventricular systolic function. AIMS: To determine the pulsed Doppler DTI-pattern in patients with heart failure and to examine whether it has a similar capacity as MPWD and AVPD to diagnose diastolic dysfunction. METHODS: We studied 15 controls without congestive heart failure (CHF), 15 patients with diastolic (EF>45%+CHF) and 15 patients with systolic (EF<35%+CHF) left ventricular dysfunction and CHF. RESULTS: The DTI maximal velocities during systole (s), early filling wave (e) and atrial filling wave (a), decrease with reduced left ventricular ejection fraction, r=0.75, r=0.56 and r=0.66 (P<0.001) and regional isovolumetric contraction and intraventricular relaxation time measured by DTI are prolonged, r=0.59 and r=0.73, respectively (P<0.001). The 15 patients with diastolic heart failure were identified by MPWD or DTI but only 11 by AVPD with 8, 10 and 9 false-positive, respectively (P<0.01, P<0.05 and NS). CONCLUSIONS: Regional DTI show a consistent pattern in patients with left ventricular dysfunction and heart failure. Regional DTI has similar accuracy as MPWD in identifying diastolic heart failure patients and is superior to the AVPD technique. DTI may be a useful diagnostic tool in diastolic heart failure patients.

Diagnostic tests, treatment and follow-up in heart failure patients--is there a gender bias in the coherence to guidelines?

AIMS: To relate clinical data in a consecutive cohort of patients admitted with heart failure in Sweden to demographic data and the use of diagnostic tests, medical treatment, care process and mortality. METHODS AND RESULTS: Retrospective investigation of all charts concerning patients discharged with primary diagnosis of heart failure in two Swedish hospitals during the second half of 1995 was undertaken. Records from 187 men and 192 women were analyzed, median age was 78 years. During hospital stay 75% of the patients, regardless of gender, were examined with chest radiography. Echocardiography was performed in 59% of all patients, more often in men than in women (68% vs. 55%, P<0.011). The proportion of patients receiving ACE-inhibitors was higher if echocardiography had been performed, in both men (38% vs. 72%, P<0.001) and women (38% vs. 55%, P<0.033). Mean hospital stay was 6.4 days. After discharge 57% of the patients were referred to the general practitioners (GP), 21% to the hospital outpatient clinic. Young age (P<0.001), male gender (P<0.01) and treatment with beta-blocking agents (P<0.035) were independently related to referral to hospital outpatient clinic. Within the group referred to the GPs, 62% of the patients had a follow-up visit within 3 months after discharge while 49% had visited the hospital outpatient clinic. The 1-year mortality rate was high, 30%. CONCLUSION: Patients admitted with heart failure in Sweden are old and carry a poor prognosis. In spite of the poor prognosis, only approximately half of the patients are followed-up within 3 months after discharge. There is, in contrast to practice guidelines, an underuse of diagnostic tests of left ventricular function and medical treatment is often suboptimal. These unsatisfactory findings were more pronounced in women.

Effect of carvedilol on diastolic function in patients with diastolic heart failure and preserved systolic function. Results of the Swedish Doppler-echocardiographic study (SWEDIC).

AIM: The purpose of this study was to investigate the effects of carvedilol on diastolic function (DF) in heart failure patients with preserved left ventricular (LV) systolic function and abnormal DF. PATIENTS AND METHODS: We randomised 113 patients with diastolic heart failure (DHF) (symptomatic, with normal systolic LV function and abnormal DF) into a double blind multi-centre study. The patients received either carvedilol or matching placebo in addition to conventional treatment. After uptitration, treatment was continued for 6 months. Two-dimensional and Doppler echocardiography were used for quantification of LV function at baseline and at follow-up. Four different DF variables were evaluated by Doppler echocardiography: mitral flow E:A ratio, deceleration time (DT), isovolumic relaxation time (IVRT) and the ratio of systolic/diastolic pulmonary venous flow velocity (pv-S/D). Primary endpoint was change in the integrated quantitative assessment of all four variables during the study. RESULTS: Ninety-seven patients completed the study. A mitral flow pattern reflecting a relaxation abnormality was recorded in 95 patients. There was no effect on the primary endpoint, although a trend towards a better effect in carvedilol treated patients was noticed in patients with heart rates above 71 beats per minute. At the end of the study, there was a statistically significant improvement in E:A ratio in patients treated with carvedilol (0.72 to 0.83) vs. placebo (0.71 to 0.76), P<0.05. CONCLUSIONS: Treatment with carvedilol resulted in a significant improvement in E:A ratio in patients with heart failure due to a LV relaxation abnormality. E:A ratio was found to be the most useful variable to identify diastolic dysfunction in this patient population. This effect was observed particularly in patients with higher heart rates at baseline.

Comparison of electrocardiograms recorded with standard leads and derived from the vectorcardiographic frank leads in high risk patients.

Dynamic vectorcardiography (VCG) is increasingly employed for ischaemia monitoring with the use of a computerized method for recording and on-line analysis by the calculation of trend parameters. To elucidate how well the derived electrocardiogram (dECG), calculated from the VCG, compares with the simultaneously registered standard ECG (sECG), dECGs from 17 postoperative cardiac-risk patients and 36 subjects with acute myocardial infarction (AMI) were compared to sECGs, both quantitatively in leads II, III, V2 and V5 and qualitatively. Despite small, but some significant differences, mainly in the amplitudes of precordial leads, the qualitative interpretation by two independent cardiologists showed good agreement between the methods (kappa = 0.72 and 0.67, respectively) for the diagnosis of AMI/ischaemia. The dECG seems to be reliable and can be used clinically in these groups of patients during VCG recordings.

Computerized vectorcardiography for improved perioperative cardiac monitoring in vascular surgery.

BACKGROUND: Postoperative cardiac complications occur frequently after noncardiac operations in high-risk patients. Routine cardiac monitoring is usually done by electrocardiographic (ECG) methods. The present analysis shows that computerized vectorcardiography (VCG) is superior to traditional ECG monitoring in predicting postoperative cardiac complications. STUDY DESIGN: Thirty-eight patients scheduled for abdominal aortic operations were monitored intraoperatively and for 48 hours postoperatively using VCG. These data were analyzed in a blinded fashion, and compared to cardiac outcome and regularly calculated 12-lead ECGs. RESULTS: Thirteen patients suffered from cardiac events: myocardial infarction (n = 3), cardiac death (n = 1), recurrent myocardial ischemia (n = 1), arrhythmias (n = 2), congestive heart failure (n = 2), and arrhythmias combined with congestive heart failure (n = 4). Thirty of 38 patients had ischemia recorded on their VCG, including all 13 patients with cardiac events. Only seven of the 13 patients had ischemic changes on the V5-lead alone and ten on the three leads II, V4, V5, yielding a sensitivity of 54 percent (V5), 77 percent (II, V4, V5) and 100 percent (VCG). Signs of ischemia appeared 400 +/- 690 (mean plus or minus standard deviation) minutes earlier (median 78 minutes, with a range of zero to 2,284 minutes), and never later on the VCG compared to the three leads II, V4, V5. CONCLUSIONS: Vectorcardiography in this risk group shows increased sensitivity in predicting perioperative cardiac complications and earlier ischemia detection than the most sensitive scalar leads. Vectorcardiography substantially improves the possibility of earlier intervention, potentially reducing the incidence of postoperative cardiac complications.

Blood pressure and left ventricular geometric pattern determine diastolic function in hypertensive myocardial hypertrophy.

Abnormal left ventricular (LV) diastolic relaxation is an early sign of hypertensive heart disease. Whether LV diastolic dysfunction is caused directly by raised blood pressure, or by structural changes related to LV hypertrophy remains controversial. We examined 115 hypertensive patients with LV hypertrophy, and two age- and gender-matched groups (38 hypertensive patients without LV hypertrophy and 38 normotensive subjects) by echocardiography to assess determinants of LV diastolic function, and the relation between diastolic function and LV geometric pattern. Diastolic function was evaluated by the E/A-ratio, E wave deceleration time (E-dec), isovolumic relaxation time (IVRT), and the atrioventricular plane displacement method (AV-LA/AV-mean). A multivariate analysis (including gender, age and body mass index) shows diastolic function to be inversely related to blood pressure, LV wall thickness and LV mass, but not to LV end diastolic diameter. The E/A-ratio generally showed the strongest relations. Only the E/A-ratio and AV-LA/AV-mean were related to heart rate. By stepwise regression analysis, age was the strongest determinant for the E/A-ratio, E-dec and AV-LA/AV-mean, followed by systolic blood pressure, heart rate and LV wall thickness. For IVRT, however, LV wall thickness appeared strongest, followed by systolic blood pressure and age. In conclusion, blood pressure and LV wall thickness both have independent influence on LV diastolic function. Age and blood pressure are the most important factors to determine the E/A-ratio and E-dec, whereas LV geometry and blood pressure are most important when IVRT is used. AV-LA/AV-mean may not be useful in hypertensive LV hypertrophy.

Effect of enalapril initiated early after acute myocardial infarction on heart failure parameters, with reference to clinical class and echocardiographic determinants. CONSENSUS II Multi-Echo Study Group.

BACKGROUND AND HYPOTHESIS: Although the angiotensin-converting enzyme inhibitor enalapril has recently been shown to reduce mortality and the need for hospitalization in patients with left ventricular dysfunction and congestive heart failure, this drug was found to have no significant impact on short-term mortality after acute myocardial infarction (AMI) in the CONSENSUS II trial. The effect of enalapril initiated early after AMI on clinical and echocardiographic determinants of left ventricular (LV) function was studied in a subset of patients from CONSENSUS II. METHODS: Symptoms and signs of heart failure were classified as NYHA and dyspnea classes. Echocardiography included LV end-systolic volumes (ESV) and end-diastolic volumes (EDV), as well as ejection fraction (EF), wall motion index (WMI), and mitral flow indices. In all, 428 patients were included and followed for an average of 5.1 months by serial examinations, starting 2-5 days after myocardial infarction (MI) and repeated after 1 month and at the completion of the study. RESULTS: There was no beneficial effect of enalapril on clinically determined function. Changes (i.e., changes in NYHA class) in the functional status remained correlated with changes in echocardiographic determinants throughout the study in patients belonging to the placebo group: EDV index (r = 0.36, p = 0.002, ESV index (r = 0.49, p < 0.001), EF (r = -0.41, p < 0.001), and WMI (r = 0.29, p = 0.008). In a stepwise logistic regression model, the best baseline parameters to predict NYHA class at final visit in all patients were age (p = 0.014) and ESV index (p = 0.001). CONCLUSION: Enalapril treatment for an average period of 5.1 months following MI resulted in no clinically significant beneficial effects on NYHA and dyspnea class. Changes in clinical function class were correlated with changes in echocardiographic determinants in placebo-treated patients, but not in patients given enalapril.

Serum digoxin concentration: increase after rest in different body positions.

If outpatients are allowed to rest in the supine position before their blood is sampled, serum digoxin increases. In a recent study, the serum digoxin concentration after 2-h standardized supine rest correlated better with the clinical status of patients than the value before rest. In the present study, 21 outpatients were studied on 2 consecutive days, approximately 24 h after the latest dose of digoxin. Blood samples for the assay of serum digoxin were taken on arrival at the department and after 1.5- and 2-h rest either supine or sitting (random order). The increases after 1.5-h rest were 12% (0-25%; p less than 0.001) and 12% (-3-47%; p less than 0.001), supine and sitting, respectively. The respective increases after 2-h rest were 14% (-11-32%; p less than 0.001) and 16% (0-74%; p less than 0.001). There were no statistically significant differences between the increases in serum digoxin concentration after supine and sitting rest. These results make it possible to recommend standardized rest in the sitting position (1.5-2 h) for outpatients before blood samples are collected when reliable serum digoxin analyses are of importance.

Oral salbutamol decreases serum digoxin concentration.

The effect of a therapeutic dose of oral salbutamol on serum and skeletal muscle digoxin concentrations has been studied in volunteers digitalised with digoxin. On one occasion a biopsy was taken from the quadriceps after 2 h of supine rest and then 3-4 mg salbutamol was given orally. Blood samples were taken before and after that dose and another muscle biopsy specimen was taken from the same thigh 180 min after the medication. On another occasion control blood sampling, ECG and blood pressure recordings were made but without muscle biopsies or salbutamol administration. Compared to the control measurements, salbutamol decreased the serum digoxin concentration (0.30 nmol.l-1). It also reduced the serum potassium concentration (0.58 mmol.l-1). The digoxin concentration in skeletal muscle did not change significantly after the intake of salbutamol. Thus, even a therapeutic oral dose of salbutamol reduces the serum digoxin concentration in man.

Effect of salbutamol on digoxin concentration in serum and skeletal muscle.

Beta 2-receptor stimulation has been reported to increase the concentration of 3H-ouabain in rat skeletal muscle. The present study was undertaken to see if beta 2-adrenoceptor stimulation by i.v. injection of salbutamol had any influence on the pharmacokinetics of digoxin in man. Ten volunteers were digitalized with digoxin and were investigated on two occasions. On each occasion a muscle biopsy was taken from the quadriceps after 2 h of supine rest. An injection of salbutamol 4 micrograms.kg-1 b.wt. or saline was then given intravenously. Blood samples were taken before and after the injection and further muscle biopsy was taken from the same thigh 120 min after the injection. Compared to the injection of saline, salbutamol caused a decrease in the serum digoxin and potassium concentrations. The change in serum potassium was significantly correlated with that in digoxin. The digoxin concentration in skeletal muscle was not significantly changed by either the salbutamol or saline injections.

Effect of physical activity on the day-to-day variation in serum digoxin concentration.

Physical exercise has been found to increase digoxin binding in working skeletal muscle along with a concomitant decrease in serum digoxin concentration. In a recent study on healthy volunteers, moderate physical activity during maintenance digoxin treatment was shown to decrease the renal excretion of digoxin secondary to this redistribution of the drug, thereby affecting the body content of digoxin. In the present study the influence of changes in everyday physical activities, carried out during a 10-h period after ingestion of the daily maintenance digoxin dose, on the steady-state serum digoxin concentration (24 h after the last dose) was studied in 10 digoxin-treated outpatients (61-81 years of age). Compared to normal daily activity, complete bed rest for 10 h after ingestion of the maintenance dose did not affect the steady-state serum digoxin concentration. The lack of such an influence may be explained either by a low degree of everyday physical activity in the investigated patients or to a compensatory increase in the renal excretion of digoxin during the night preceding the serum digoxin measurement. Thus, standardization of physical activity 1-2 h before blood sampling is adequate when analysing the serum digoxin concentration in elderly outpatients.