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Because myocardial hypertrophy is an independent risk factor for sudden death and cardiac failure, it is important to understand its molecular mechanisms to be able to devise new treatment strategies in the future. Stretch is the putative primary stimulus triggering hypertrophy. Further signal transduction steps such as auto- and paracrine secretion of growth factors or transmission via the cytoskeleton are beginning to be unravelled. Subsequent to hypertrophic stimuli some important proteins undergo an isoform switch; questitatively, however, the most important step is an increase in translational capacity for each mRNA. Myocardial specific gene expression is achieved by coordinate interaction of several transcription factors, some of which may be involved in nuclear transmission of hypertrophic signals. One of the genes capable of transmitting hypertrophic signals is the "early growth response gene-1 (Egr-1)". We have also shown that nuclear estrogen receptors act as transcription factors in the myocardium and may therefore be involved in the sex-specific modulation of cardiac hypertrophy. At present, pharmacological interventions aiming at reduction of hypertrophy by interfering with the signal transduction pathway from the membrane to the nucleus are actively being sought. These transduction pathways are composed of a series of proteinkinases which may be amenable to drugs. In the future, gene transfer may become an option for treatment.

In the present study the prognostic value of ANP measurement was investigated in 52 patients undergoing coronary angiography. 22 normotensive and 30 hypertensive subjects were included. A significant inverse correlation between left ventricular ejection fraction (EF) and plasma ANP was found in normotensives, but not in hypertensives. In patients with chronic myocardial infarction, there was no difference in ANP levels compared to patients without infarction in either group, provided that EF was normal. However, hypertensives showed a 35% increase in ANP compared to normotensives. This was true for subjects with and without myocardial infarction. These results show that in normotensives ANP levels have a prognostic value on a statistical rather than an individual basis. This does not apply to hypertensives, whose ANP level is increased by factors other than impaired ejection fraction.

In 42 patients with heart failure who were on long-term treatment with flecainide (2 X 100 mg daily by mouth) plasma concentration of flecainide was measured before the morning dose and compared with the clinical grade of heart failure or left ventricular ejection fraction (in the levo-angiogram). Mean plasma flecainide concentration was 415 +/- 244 ng/ml (110-1035 ng/ml), mean ejection fraction 55 +/- 17.7% (24-84%) (r = -0.60). In seven patients with plasma concentrations over 700 ng/ml (870 +/- 150 ng/ml) in clinical grade III or IV, ejection fractions were 24, 25, 25, 30, 33, 37 and 44%, respectively. In two patients (ejection fraction of 24 and 25%, respectively) the morning plasma concentration was around 1000 ng/ml. The results point to possible high plasma flecainide concentrations--at times in the toxic range--in patients who are in heart failure. In patients with marked reduction in left ventricular pumping function who are on long-term flecainide treatment, a reduction in dosage or monitoring of plasma flecainide concentration is indicated.

It is well established that information on their disease is one of the prerequisites for improvement of patients' compliance with therapy. The authors have therefore developed a simple slide program presenting information on hypertension and obesity. Consisting of 52 slides, it was shown in the central waiting room of the medical outpatient department at the University Hospital, Zurich. In order to assess learning, 841 patients were asked to fill in a questionnaire. 485 had seen the program and 356 served as controls with the program switched off. Four main results emerged: 1. The percentage of subjects scoring greater than or equal to 4 correct answers (of a maximum of 5) rose significantly from 22.6% to 64.2%. 2. The number of incorrect answers (maximum 3) remained unchanged. 3. Learning decreased with age. 4. Occupation did not have a significant effect on learning. The results clearly show that the program represents an effective method of teaching patients and may therefore serve to improve compliance with therapy.

The role of atrial natriuretic peptide (ANP) in the pathogenesis of essential hypertension has not yet entirely been clarified. We investigated whether the increase of ANP in essential hypertension may be explained by elevated right atrial pressures and/or a different relationship between right atrial pressures and ANP secretion. Patients with stable essential hypertension undergoing right and left heart catheterization because of suspected coronary heart disease had significantly higher ANP levels than normotensives: 58.7 +/- 6.7 pg/ml in hypertensives versus 42.0 +/- 4.1 pg/ml in normotensives (p less than 0.01). Matching hypertensives with normotensives at identical levels of left ventricular enddiastolic pressure revealed significantly higher mean pulmonary artery pressures in hypertensives. Right atrial diastolic pressure (v-wave) after matching for LVEDP was 4.8 +/- 0.5 mm Hg in hypertensives and 3.1 +/- 0.2 mm Hg in normotensives (p less than 0.05). In addition, at any given mean right atrial pressure hypertensives showed higher ANP levels than normotensives. These results demonstrate that hypertensives exhibit raised pressures in the pulmonary artery independent of left ventricular pressure load. The elevation in right atrial pressures and the steeper relationship between these pressures and ANP are a suitable explanation for raised ANP levels in hypertension. ANP in essential hypertension may represent a counterregulation against elevated pulmonary resistance.

In this study plasma levels of atrial natriuretic peptide and of the catecholamines epinephrine and norepinephrine were investigated in hypertensive patients (HT) (n = 30). 22 normotensive patients (NT) served as controls. Hypertensives showed an elevated ANP-level in comparison with controls (46.8 +/- 3.3 vs. 36.8 +/- 3.3 pg/ml, M +/- SEM, p less than 0.01). When patients with myocardial infarction or with reduced ejection fraction were excluded, the same relation was demonstrated (49.3 +/- 3.2 vs. 33.6 +/- 2.0 pg/ml, p less than 0.01). Plasma norepinephrine was 230.8 +/- 52.3 pg/ml in HT compared with 138.0 +/- 19.6 pg/ml in NT (p less than 0.05). Epinephrine was 70.8 +/- 10.5 vs. 54.8 +/- 9.7 pg/ml in HT and NT. To exclude an increased left ventricular enddiastolic - and hence left atrial - pressure as the cause for the elevation of ANP and norepinephrine, HT and NT were matched for the same levels of enddiastolic pressure (LVEDP) (n = 18). For each level of LVEDP ANP was higher in HT than in NT (p less than 0.01). The same held true for norepinephrine (p less than 0.05) and to a lesser extent for epinephrine (p = 0.09). Our results demonstrate that patients with essential hypertension exhibit markedly elevated levels for ANP and catecholamines which is not due to myocardial failure. We propose that the increased secretion of the vasodilatory hormone ANP serves as counterregulation against the vasoconstrictor norepinephrine. The endocrine function of the heart may play a pivotal role in the modulation of sympathetic activity.

Unlabelled: Only the free protein-unbound drug concentration in plasma is pharmacologically active. The concentration of some drugs in saliva is equal to the free drug level. We compared concentrations (in plasma before, 30 and 60 min after the morning dose, in saliva before, 30, 60, 90 and 120 min after the morning dose) of amiodarone (n = 8, 2 x 200 mg orally per day) and flecainide (n = 16, 2 x 100 mg) administered as chronic antiarrhythmic treatment. Drug levels were measured by "high performance liquid chromatography"., Results: Just prior to the first morning dose, amiodarone concentrations in plasma were 1.0-2.9 (2.0 +/- 0.6) micrograms/ml, in saliva 0.02-0.25 micrograms/ml; flecainide in plasma 80-560 (316 +/- 163) ng/ml, in saliva 630-3700 (1749 +/- 963) ng/ml. After the morning dose we found maximal flecainide plasma levels of 462 +/- 203 and saliva levels of 3218 +/- 2857 ng/ml. The highest flecainide concentrations in the saliva (13,400 and 11,300 ng/ml) were found in two patients 30 and 60 min after the morning dose. Flecainide, but not amiodarone, is excreted actively in the saliva, probably indicating an enteroenteric circulation. This should be considered to reduce life-threatening flecainide intoxications by gastric and intestinal lavage and suction. The concentration of flecainide in the saliva does not represent the non-protein-bound free drug level in the plasma.