[Sexual activity in ischemic heart disease. Risk and therapeutic possibilities]. / Seksuel aktivitet ved iskaemisk hjertesygdom. Risiko og behandlingsmuligheder.

A major concern of patients with ischaemic heart disease is whether sexual activity is safe. In addition, patients are often reluctant to discuss sexual problems, including erectile dysfunction. Fear of sexual failure or fear of an acute ischaemic cardiac event as a result of sexual activity may create anxiety and lead to avoidance of sexual activity, which can significantly affect quality of life. In patients with a recent acute myocardial infarction the participation in a cardiac rehabilitation program should be strongly encouraged. The results are an improvement in physical capacity and self confidence. The performance of an exercise test at the time of hospital discharge following acute myocardial infarction is mandatory, and can be used in both risk stratification and cardiac rehabilitation. Patients who can manage a work capacity of at least 100 Watt without evidence of myocardial ischaemia or arrhythmias may without concerns take part in an active sexual life. Comprehensive information and appropriate use of pharmacologic agents for erectile dysfunction can add significantly to quality of life.

[Dofetilide to patients with heart failure and left ventricular dysfunction]. / Dofetilid til patienter med hjerteinsufficiens og dårligt fungerende venstre ventrikel.

INTRODUCTION: Dofetilide, a new class III antiarrhythmic drug, was tested for its ability to reduce mortality and morbidity in patients with congestive heart failure and left ventricular dysfunction. METHODS: In 34 Danish centers, 1518 patients with NYHA class III or IV heart failure and wall motion index of the left ventricle < or = 1.2 (ejection fraction < or = 35%) were randomized to receive dofetilide or placebo in a double blind study. The dose of dofetilide was adjusted to renal function and the QT interval. Patients were monitored continuously with ekg during the first three days in the study. Minimum follow up was one year. RESULTS: Dofetilide did not affect mortality. Hospitalizations for worsening of heart failure were reduced significantly, hazard ratio 0.75 (0.63-0.89) Dofetilide effectively converted atrial fibrillation to sinus rhythm. After one year, 61% of patients with atrial fibrillation had converted on dofetilide and 33% on placebo (p < 0.001). DISCUSSION: Dofetilide can be used to convert atrial fibrillation to sinus rhythm and to maintain sinus rhythm in patients with congestive heart failure and left ventricular dysfunction. Dofetilide does not affect mortality.

Effect of dofetilide in patients with recent myocardial infarction and left-ventricular dysfunction: a randomised trial.

BACKGROUND: Arrhythmias cause much morbidity and mortality after myocardial infarction, but in previous trials, antiarrhythmic drug therapy has not been convincingly effective. Dofetilide, a new class III agent, was investigated for effects on all-cause mortality and morbidity in patients with left-ventricular dysfunction after myocardial infarction. METHODS: In 37 Danish coronary-care units, 1510 patients with severe left-ventricular dysfunction (wall motion index < or = 1.2, corresponding to ejection fraction < or = 0.35) were enrolled in a randomised, double-blind study comparing dofetilide (n=749) with placebo (n=761). The primary endpoint was all-cause mortality. Secondary endpoints included cardiac and arrhythmic mortality and total arrhythmic deaths. Analyses were by intention to treat. FINDINGS: No significant differences were found between the dofetilide and placebo groups in all-cause mortality (230 [31%] vs 243 [32%]), cardiac mortality (191 [26%] vs 212 [28%]), or total arrhythmic deaths (129 [17%] vs 140 [18%]). Atrial fibrillation or flutter was present in 8% of the patients at study entry. In these patients, dofetilide was significantly better than placebo at restoring sinus rhythm (25 of 59 vs seven of 56; p=0.002). There were seven cases of torsade de pointes ventricular tachycardia, all in the dofetilide group. INTERPRETATION: In patients with severe left-ventricular dysfunction and recent myocardial infarction, treatment with dofetilide did not affect all-cause mortality, cardiac mortality, or total arrhythmic deaths. Dofetilide was effective in treating atrial fibrillation or flutter in this population.

Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group.

BACKGROUND: Atrial fibrillation occurs frequently in patients with congestive heart failure and commonly results in clinical deterioration and hospitalization. Sinus rhythm may be maintained with antiarrhythmic drugs, but some of these drugs increase the risk of death. METHODS: We studied 1518 patients with symptomatic congestive heart failure and severe left ventricular dysfunction at 34 Danish hospitals. We randomly assigned 762 patients to receive dofetilide, a novel class III antiarrhythmic agent, and 756 to receive placebo in a double-blind study. Treatment was initiated in the hospital and included three days of cardiac monitoring and dose adjustment. The primary end point was death from any cause. RESULTS: During a median follow-up of 18 months, 311 patients in the dofetilide group (41 percent) and 317 patients in the placebo group (42 percent) died (hazard ratio, 0.95; 95 percent confidence interval, 0.81 to 1.11). Treatment with dofetilide significantly reduced the risk of hospitalization for worsening congestive heart failure (risk ratio, 0.75; 95 percent confidence interval, 0.63 to 0.89). Dofetilide was effective in converting atrial fibrillation to sinus rhythm. After one month, 22 of 190 patients with atrial fibrillation at base line (12 percent) had sinus rhythm restored with dofetilide, as compared with only 3 of 201 patients (1 percent) given placebo. Once sinus rhythm was restored, dofetilide was significantly more effective than placebo in maintaining sinus rhythm (hazard ratio for the recurrence of atrial fibrillation, 0.35; 95 percent confidence interval, 0.22 to 0.57; P<0.001). There were 25 cases of torsade de pointes in the dofetilide group (3.3 percent) as compared with none in the placebo group. CONCLUSIONS: In patients with congestive heart failure and reduced left ventricular function, dofetilide was effective in converting atrial fibrillation, preventing its recurrence, and reducing the risk of hospitalization for worsening heart failure. Dofetilide had no effect on mortality.

Dynamics of spectral components of heart rate variability during changes in autonomic balance.

Frequency domain analysis of heart rate variability (HRV) has been proposed as a semiquantitative method for assessing activities in the autonomic nervous system. We examined whether absolute powers, normalized powers, and the low frequency-to-high frequency ratio (LF/HF) derived from the HRV power spectrum could detect shifts in autonomic balance in a setting with low sympathetic nervous tone. Healthy subjects were examined for 3 h in the supine position during 1) control conditions (n = 12), 2) acute beta-blockade (n = 11), and 3) chronic beta-blockade (n = 10). Heart rate fell during the first 40 min of the control session (72 +/- 2 to 64 +/- 2 beats/min; P < 0. 005) and was even lower during acute and chronic beta-blockade (56 +/- 2 beats/min; P < 0.005). The powers of all spectral areas rose during the first 60 min in all three settings, more so with beta-blockade (P < 0.05). LF/HF was found to contain the same information as powers expressed in normalized units. LF/HF detected the shift in autonomic balance induced by beta-blockade but not the change induced by supine position. In conclusion, none of the investigated measures derived from power spectral analysis comprehensively and consistently described the changes in autonomic balance.

Novel donor splice site mutation in the KVLQT1 gene is associated with long QT syndrome.

INTRODUCTION: Inherited long QT syndrome (LQTS) recently has been associated with mutations in genes coding for potassium (KVLQT1, KCNE1, and HERG) or sodium (SCN5A) ion channels involved in regulating either sodium inward or potassium outward currents of heart cells, resulting in prolongation of the repolarization period. We describe a new mutation, a -1 donor splice site mutation in a kindred with two affected members (QTc = 0.61 and 0.54 sec). METHODS AND RESULTS: Single stranded conformation polymorphism (SSCP) analyses were performed on DNA fragments amplified by polymerase chain reaction from DNA extracted from whole blood. Aberrant conformers were analyzed by DNA sequencing. SSCP analysis of the KVLQT1 gene revealed an aberrant conformer in the affected family members. DNA sequencing confirmed the presence of a G-->A change in the last nucleotide of codon 344. This mutation does not cause an amino acid change, but a change of the splice site characteristics at the 3' end of exon 6. The mutation may affect, through deficient splicing, the putative sixth transmembrane segment of the K+ channel, and this type of mutation has not previously been described in KVLQT1. CONCLUSION: The clinical course of LQTS in the affected family members, in whom no deaths occurred despite 20 to 30 syncopes, can be explained by the ability of the cellular machinery to perform partial correct splicing in the mutant allele. This type of mutation may be misinterpreted as a normal variant, since it is a point mutation causing neither an amino acid change nor the introduction of a stop codon.

Unexpected lability of cysteine acetamidomethyl thiol protecting group. Tyrosine ring alkylation and disulfide bond formation upon acidolysis.

Cleavage and deprotection of the peptidyl resin H-Asn-Gly-Gly-Cys (Acm)-Glu(OBu(t))-Gln-Tyr(Bu(t))-Cys(Acm)-Ser(Bu(t))-Asp( OBU(t))-[(p-alkoxy)benzyloxy polystyrene resin] using standard conditions with various trifluoroacetic acid-containing mixtures were found to result in partial removal of ordinarily acid-stable S-Acm groups. Thus, apart from the desired peptide H-Asn-Gly-Gly-Cys (Acm)-Glu-Gln-Tyr-Cys(Acm)-Ser-Asp-OH, a disulfide-cyclic peptide derivative was also isolated. Furthermore, it was found that in another major by-product of the peptide resin cleavage the tyrosine side chain had been alkylated with an Acm group in a position ortho to the phenolic function. The formation of both by-products could be suppressed by carrying out the cleavage/deprotection reaction at higher dilution and by inclusion of scavengers such as phenol. An authentic sample of the disulfide-cyclic peptide was obtained by oxidation of H-Asn-Gly-Gly-Cys-Glu-Gln-Tyr-Cys-Ser-Asp-OH using Ellman's reagent.

Influence of forced respiration on nonlinear dynamics in heart rate variability.

Although it is doubtful whether the normal sinus rhythm can be described as low-dimensional chaos, there is evidence for inherent nonlinear dynamics and determinism in time series of consecutive R-R intervals. However, the physiological origin for these nonlinearities is unknown. The aim of this study was to test whether the known nonlinear input from spontaneous respiration is a source for the nonlinearities in heart rate variability. Twelve healthy subjects were examined in supine position with 3-h electrocardiogram recordings during both spontaneous and forced respiration in accordance with a metronome set to 12 min(-1). Nonlinear dynamics were measured as the correlation dimension and the nonlinear prediction error. Complexity expressed as correlation dimension was unchanged from normal respiration, 9.1 +/- 0.5, compared with forced respiration, 9.3 +/- 0.6. Also, nonlinear determinism expressed as the nonlinear prediction error did not differ between spontaneous respiration, 32.3 +/- 3.4 ms, and forced respiration, 31.9 +/- 5.7. It is concluded that the origin of the nonlinear dynamics in heart rate variability is not a nonlinear input from the respiration into the cardiovascular oscillator. Additional studies are needed to elucidate the mechanisms behind the nonlinear dynamics in heart rate variability.

Dose-related decrease of serum coenzyme Q10 during treatment with HMG-CoA reductase inhibitors.

Coenzyme Q10 (ubiquinone) the essential mitochondrial redox-component and endogenous antioxidant, packaged into the LDL + VLDL fractions of cholesterol, has been suggested as an important anti-risk factor for the development of atherosclerosis as explained by the oxidative theory. Forty-five hypercholesterolemic patients were randomized in a double-blind trial in order to be treated with increasing dosages of either lovastatin (20-80 mg/day) or pravastatin (10-40 mg/day) over a period of 18 weeks. Serum levels of coenzyme Q10 were measured parallel to the levels of cholesterol at baseline on placebo and diet and during active treatment. A dose-related significant decline of the total serum level of coenzyme Q10 was found in the pravastatin group from 1.27 +/- 0.34 at baseline to 1.02 +/- 0.31 mmol/l at the end of the study period (mean +/- S.D.), P < 0.01. After lovastatin therapy the decrease was significant as well and more pronounced, from 1.18 +/- 0.36 to 0.84 +/- 0.17 mmol/l, P < 0.001. Although HMG-CoA reductase inhibitors are safe and effective within a limited time horizon, continued vigilance of a possible adverse consequence from coenzyme Q10 lowering seems important during long-term therapy.

Structure-activity relationships of novel hematoregulatory peptides.

Hematopoiesis is a lifelong cell renewal process regulated by a family of lineage specific hematopoietic growth factors. Several hematopoietic growth factors such as G-CSF, GM-CSF, and M-CSF have been clinically evaluated for enhancement of host defense in normal and immunocompromised patients and for the treatment of infectious diseases. This paper reports the structure-activity relationships of low molecular weight hematoregulatory peptides based on a nonapeptide (1, SK&F 107647). Like the macromolecular growth factors, these peptides modulate host defense. A molecular target for this class of compounds has not yet been identified. However, the structure-activity relationships established by this study implicate a very specific molecular recognition event that is pivotal for the biological activities of 1 and its analogues.

Short- and long-term variations in non-linear dynamics of heart rate variability.

OBJECTIVES: The purpose of the study was to investigate the short- and long-term variations in the non-linear dynamics of heart rate variability, and to determine the relationships between conventional time and frequency domain methods and the newer non-linear methods of characterizing heart rate variability. METHODS: Twelve healthy subjects were investigated by 3-h ambulatory ECG recordings repeated on 3 separate days. Correlation dimension, non-linear predictability, mean heart rate, and heart rate variability in the time and frequency domains were measured and compared with the results from corresponding surrogate time series. RESULTS: A small significant amount of non-linear dynamics exists in heart rate variability. Correlation dimensions and non-linear predictability are relatively specific parameters for each individual examined. The correlation dimension is inversely correlated to the heart rate and describes mainly linear correlations. Non-linear predictability is correlated with heart rate variability measured as the standard deviation of the R-R intervals and the respiratory activity expressed as power of the high-frequency band. The dynamics of heart rate variability changes suddenly even during resting, supine conditions. The abrupt changes are highly reproducible within the individual subjects. CONCLUSIONS: The study confirms that the correlation dimension of the R-R intervals is mostly due to linear correlations in the R-R intervals. A small but significant part is due to non-linear correlations between the R-R intervals. The different measures of heart rate variability (correlation dimension, average prediction error, and the standard deviation of the R-R intervals) characterize different properties of the signal, and are therefore not redundant measures. Heart rate variability cannot be described as a single chaotic system. Instead heart rate variability consists of intertwined periods with different non-linear dynamics. It is hypothesized that the heart rate is governed by a system with multiple "strange" attractors.

Effect of systemic treatment with cholesterol-lowering drugs on the skin barrier function in humans.

The intercellular lipids of stratum corneum are predominantly formed by cholesterol, ceramides and free fatty acids. Cholesterol synthesis is inhibited by statins, cholesterol-lowering drugs (lovastatin, pravastatin, simvastatin). The present study was undertaken to examine the effect of these drugs on skin barrier function. Knowledge about the effect on epidermis of systemic inhibition of cholesterol synthesis may improve our understanding of the skin barrier function. Seventeen statin-treated subjects were compared to controls. All were patch-tested with sodium lauryl sulphate (SLS), and the skin was evaluated after 24 h and after 7 days by measurement of transepidermal water loss (TEWL), erythema and visual scoring. After 24 h as well as after one week erythema was significantly less pronounced in the statin-treated group than in controls (p < 0.001). No significant differences in TEWL were found between the groups at any time. The results imply a decreased bioavailability of SLS in the statin-treated group, while no evidence for an altered permeability barrier to water was found.

Lack of evidence for low-dimensional chaos in heart rate variability.

INTRODUCTION: The term chaos is used to describe erratic or apparently random time-dependent behavior in deterministic systems. It has been suggested that the variability observed in the normal heart rate may be due to chaos, but this question has not been settled. METHODS AND RESULTS: Heart rate variability was assessed by recordings of consecutive RR intervals in ten healthy subjects using ambulatory ECG. All recordings were performed with the subjects at rest in the supine position. To test for the presence of nonlinearities and/or chaotic dynamics, ten surrogate time series were constructed from each experimental dataset. The surrogate data were tailored to have the same linear dynamics and the same amplitude distribution as the original data. Experimental and surrogate data were then compared using various nonlinear measures. Power spectral analysis of the RR intervals showed a 1/f pattern. The correlation dimension differed only slightly between the experimental and the surrogate data, indicating that linear correlations, and not a "strange" attractor, are the major determinants of the calculated correlation dimension. A test for nonlinear predictability showed coherent nonlinear dynamic structure in the experimental data, but the prediction error as a function of the prediction length increased at a slower rate than characteristic of a low-dimensional chaotic system. CONCLUSION: There is no evidence for low-dimensional chaos in the time series of RR intervals from healthy human subjects. However, nonlinear determinism is present in the data, and various mechanisms that could generate such determinism are discussed.

Angiotensin converting enzyme inhibition at rest and during exercise in congestive heart failure.

The haemodynamic effects of the sulfhydryl-containing angiotensin converting enzyme inhibitor, zofenopril, were studied in patients in New York Heart Association functional class II and III. Twenty-one clinically stable patients with coronary artery disease or cardiomyopathy completed a randomized double-blind treatment period of 2 months with either 15 mg zofenopril once daily or placebo. Regular therapy with digoxin and diuretic drugs was continued. Left ventricular volumes were measured by radionuclide angiography at rest and during submaximal bicycle exercise. Zofenopril significantly increased mean stroke volume at rest from 59 to 67 ml (48 vs 48 ml in the control group, 95% confidence interval of the difference 1 to 16 ml) and left ventricular ejection fraction at rest from 39 to 43% (30 vs 30% in the control group, 95% confidence interval of the difference 1 to 8%). No significant changes occurred in heart rate, cardiac output, and blood pressure at rest, and zofenopril did not result in haemodynamic alterations during exercise. Thus, 15 mg of the sulfhydryl-containing angiotensin converting enzyme inhibitor, zofenopril, administered once daily to patients with moderate heart failure increases left ventricular function at rest, but not during exercise.

Benzyloxycarbonyl-D-Phe-Pro-methoxypropylboroglycine: a novel inhibitor of thrombin with high selectivity containing a neutral side chain at the P1 position.

Thrombin, the blood-clotting enzyme, is a serine proteinase with trypsin-like specificity and is able to cleave Arg-Xaa peptide bonds but only in a very limited number of substrates (and sites therein). For the prevention and treatment of thrombosis the control of thrombin activity is a key target, and a variety of synthetic inhibitors have been introduced recently, all of which have a positive charge at the P1 site. We report the synthesis of the first example of a new class of inhibitor containing a neutral side chain at the P1 site, the peptide benzyloxycarbonyl-D-Phe-Pro- methoxypropylboroglycine. The peptide is a potent inhibitor of thrombin [Ki (limiting) = 7 nM] and is highly selective for its target enzyme in respect of other serine proteinases. This may be expected to confer considerable advantage in terms of specificity of action and reduced toxicity over conventional, positively charged, inhibitors.

[Selective screening for hypercholesterolemia. Results from a screening model in general practice]. / Selektiv screening for hyperkolesterolaemi. Resultater fra en screeningsmodel i almen praksis.

At present, it appears to be probable that both dietary changes and medicinal treatment can reduce the risk of development of coronary disease in middle-aged men with moderately to severely raised blood cholesterol values. Internationally, the limits for cholesterol intervention are considerably lower than in Denmark. Extensive cholesterol screening is, however, very expensive and the identified persons with high cholesterol values will frequently be found in sex and age groups where the beneficial effect of intervention is probably limited. A model for selective cholesterol screening in high risk groups in general practice is described here. In 20 general practices, all of the men aged 45-59 years belonging to the practice were invited to examination of cholesterol and blood pressure. Plasma cholesterol was measured by means of a Reflotron (results are available within three minutes) and the blood pressure and tobacco consumption were registered. After this, the patient's own general practitioner calculated with each of the persons the risk for development of myocardial infarction within the next ten years and intervention could be commenced immediately. 41% of those invited came for examination. Out of these, 29% had cholesterol values greater than or equal to 7.0 mmol/l (Danish limiting value), 44% greater than or equal to 6.5 mmol/l (limiting value in the remainder of Western Europe), and 5% greater than or equal to 9.0 mmol/l (severe hypercholesterolaemia) while only 18% had completely normal cholesterol less than 5.2 mmol/l. In every practice, two patients on an average were found with severe hypercholesterolaemia greater than or equal to 9.0 mmol/l. 28% of the participants had at least two of the three risk factors investigated. (ABSTRACT TRUNCATED AT 250 WORDS)

[Formalized dietary advice in hypercholesterolemia. Results in 110 men diagnosed by selective screening in general practice]. / Formaliseret diaetvejledning ved hyperkolesterolaemi. Resultater hos 110 maend diagnosticeret ved selektiv screening i almen praksis.

In connection with a screening investigation for high blood cholesterol in middle-aged men in general practice in the Municipality of Copenhagen, all participants with cholesterol values greater than or equal to 7.5 mmol/l were given brief advice by their own general practitioner and were invited to come for fasting blood lipid tests approximately ten days later. In cases with continued cholesterol greater than or equal to 6.8 mmol/l, the participants together with wives or partners were invited to formalized dietary advice in small groups. Already before the formalized dietary advice, an average decrease in serum cholesterol of 10% was observed. This was attributed to biological variation, absence of fasting, the degree of error between the measuring methods and also a genuine decrease on the basis of the brief dietary advice by the general practitioner. On control after dietary advice, a further decrease in cholesterol of 15% was observed while low density lipoprotein cholesterol fell by 20% and triglycerides by 23%. These decreases must be considered to result mainly from the dietary advice. It is concluded that a single but professional session of dietary advice in small groups and with involvement of the wives or partners is an effective method of treatment in hypercholesterolaemia. If the decrease in cholesterol obtained can be maintained, the literature suggests that the risk of development of ischaemic heart disease during the subsequent 5-7 years is reduced by 20-30%.

[Measurement of blood cholesterol, decentralized, using a Reflotron, or centralized in a laboratory. A comparison]. / Måling af blod-kolesterol decentralt med Reflotron eller centraliseret i laboratorium. En sammenligning.

In connection with an extensive screening programme for blood cholesterol, the cholesterol values in 105 participants were measured on a sample of capillary blood employing a Reflotron and, simultaneously, samples of venous blood were examined by conventional enzymatic analysis in a laboratory. Whereas the day-to-day variation and the scatter involved were quite limited in the laboratory, the variation scatter between the two methods of measurement was 0.65 mmol/l. This figure was, however, no greater than that described between different laboratories in USA. Nevertheless, it is an important problem with the Reflotron method that even slight deviations from the recommended procedure of withdrawing blood involve a systematic risk for erroneously low cholesterol results.

[Screening for cardiovascular risk factors in a large workplace]. / Screening for kardiovaskulaere risikofaktorer på en stor arbejdsplads.

A screening investigation was carried out in a large industry in the Copenhagen region and 1,472 of the employees were offered examination of blood cholesterol and measurement of blood pressure. At this examination the employees completed a one-page questionnaire about other cardiovascular risk factors. 45% of those invited participated in the investigation, the poorest participation was among women and the greatest among the male officials. On account of the limited number of female employees, the majority of results were only calculated for men. Over 1/3 of these had hypercholesteremia (greater than or equal to 7.0 mmol/l) and nearly 1/3 had, simultaneously, at least two cardiovascular risk factors in addition to age and male sex. Extensive occupational investigations under the auspices of WHO have demonstrated that energetic intervention at the place of work aimed at the cardiovascular risk factors can reduce the risk of development of coronary heart disease and death within a six-year follow-up period. It is therefore emphasized that similar interventions are very necessary also in Denmark.