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Biomedical subjects

C Linde

Publications and source records attributed to C Linde.

At least 19 recordsLinked to original sources
PubMed1999

Identification of an anti-mycobacterial domain in NK-lysin and granulysin.

NK-lysin and granulysin are homologous cationic anti-bacterial peptides produced by pig and human cytolytic lymphocytes, respectively. The solution structure of NK-lysin comprises five amphipathic alpha-helices. To investigate the properties of a helix-loop-helix region postulated to be a membrane-docking part of NK-lysin, we synthesized 22- and 29-residue peptides reproducing this region for both NK-lysin and granulysin. CD spectroscopy of the synthetic peptides in a liposomal solution showed spectra typical of alpha-helical peptides. The peptides were active against Gram-positive and Gram-negative bacteria, with the two NK-lysin peptides showing higher anti-bacterial activities than the two from granulysin. One NK-lysin peptide was active against Pseudomonas aeruginosa and Staphylococcus aureus, two organisms against which NK-lysin is inactive. Granulysin peptides were inactive against these bacteria, in contrast with granulysin, which is known to be active against them. Both NK-lysin and all synthetic analogues killed Mycobacterium tuberculosis and K562 tumour cells, but did not display haemolytic activity. These results identify a potent anti-mycobacterial domain in NK-lysin and granulysin consisting of a 22-residue (helix 3) sequence plus a disulphide-constrained loop.

Amino Acid Sequence↗
PubMed1999

[It is not easy to examine the causes of fainting. Vasovagal syncope is mostly not dangerous, cardiac syncope is potentially life-threatening].

Of the approximately 30 per cent of the population who are afflicted with syncope at some time of life, 30 per cent will relapse. Despite extensive investigation, no specific cause is identified in about one third of cases. Although some episodes of syncope, e.g. cardiovascular syncope, are benign and self-limiting, others such as mechanical cardiac syncope and arrhythmogenic syncope are associated with considerable mortality. The article consists in a review of available data on differential diagnostic evaluation and treatment with special emphasis on case history.

Age Factors↗
PubMed1999

Placebo effect of pacemaker implantation in obstructive hypertrophic cardiomyopathy. PIC Study Group. Pacing In Cardiomyopathy.

This study evaluated a possible placebo effect by pacemaker implantation. The study design was a 3-month multicenter, double-blind, randomized cross-over study to compare the effects of atrioventricular (AV) synchronous pacing with an optimal AV delay to inactive pacing in patients with obstructive hypertrophic cardiomyopathy (HC). Quality of life and left ventricular (LV) outflow tract obstruction were evaluated after the first study period in 40 patients assigned to inactive pacing. Data were compared with the corresponding results among the 41 subjects assigned to a first study period of active pacing. During inactive pacing, there was a significant improvement in perceived chest pain, dyspnea, and palpitations. Moreover, LV outflow tract gradient decreased from 71 +/- 32 mm Hg to 52 +/- 34 mm Hg (p = 0.04). In patients assigned to active pacing the reduction of the gradient was significantly more pronounced (70 +/- 24 mm Hg to 33 +/- 27 mm Hg; p <0.0001). The difference in gradient reduction between the groups was highly significant (p <0.00001). In the group assigned to active pacing there was also significant improvement in perceived symptoms as well as in alertness, the ability to be self-autonomous, and strenuous physical exercise. The improvements in the latter were significantly greater in those paced actively compared with patients paced inactively, whereas the changes in perceived symptoms did not differ between groups. In conclusion, pacemaker implantation had a placebo effect on objective and subjective parameters in this group of patients with obstructive HC.

Adult↗
PubMed1999

Rapid return of left ventricular outflow tract obstruction and symptoms following cessation of long-term atrioventricular synchronous pacing for obstructive hypertrophic cardiomyopathy.

Atrioventricular (AV) synchronous pacing reduces left ventricular (LV) outflow tract obstruction and symptoms in patients with obstructive hypertrophic cardiomyopathy (HC). The duration of gradient reduction, if pacing is discontinued for a prolonged period of time, is unknown. This question is addressed in the present randomized double-blind crossover study comparing continued with inactivated pacing. Ten patients, successfully paced for > or = 6 months, were randomized to continue pacing or to have their pacemakers inactivated after baseline examinations, including echo-Doppler imaging, exercise testing, and a quality-of-life questionnaire. When entering the study, the patients were in New York Heart Association functional classes I to II. After pacemaker programming, examinations were repeated at 1, 4, and 12 weeks. At the 12-week follow-up the alternate pacing mode was programmed, and the patient entered the second study arm. Premature pacemaker pacing occurred if severe clinical deterioration or a significant increase of the LV outflow tract obstruction were evident. Three patients started in the inactive mode and 7 patients in the active mode. All patients who started with the pacemaker inactivated required early reprogramming due to return of symptoms after 7, 10, and 13 days, respectively. All 7 patients who started in the active pacing mode completed the first period; however, after reprogramming to the inactive mode they required early activation after 1 to 20 days due to reappearance of intolerable subjective symptoms. The LV outflow tract gradient increased significantly after inactivation of pacing in all patients (22 +/- 21 mm Hg to 47 +/- 21 mm Hg). Thus, AV synchronous pacing effectively relieves symptoms and reduces the LV outflow tract gradient in patients with obstructive HC. This improvement, which is rapidly established with the initiation of cardiac pacing, is not persistent after cessation of pacing. Reinitialization of pacing promptly reduces the LV outflow tract obstruction and relieves symptoms to a preexisting extent.

Aged↗
PubMed1999

Significant improvement of quality of life following atrioventricular synchronous pacing in patients with hypertrophic obstructive cardiomyopathy. Data from 1 year of follow-up. PIC study group. Pacing In Cardiomyopathy.

AIMS: Atrioventricular synchronous pacing exerts beneficial effects, including reduction of left ventricular outflow tract gradients, in patients with hypertrophic obstructive cardiomyopathy. The Pacing in Cardiomyopathy study was initiated to explore the effects of pacing in a double-blind randomized crossover fashion. The aims were to ascertain the beneficial effects of pacing in a controlled study and to rule out a placebo effect by pacing. This paper deals with the outcome of pacing on quality of life during 1 year of follow-up. METHODS: Quality of life was evaluated with the Karolinska questionnaire, validated for patients paced for bradyarrhythmias and ischaemic heart disease. Drug-refractory patients with hypertrophic obstructive cardiomyopathy were recruited for the study and after a temporary pacing procedure implanted with permanent pacemakers. Patients were randomized to two study arms defining the sequence of pacemaker programming. In one arm the pacemaker was inactive, in the other active. After 3 months the pacemaker was reprogrammed to the alternate mode and a further 3 months followed. After this period subsequent pacemaker programming corresponded to the mode preferred by the patient. A last assessment was made 1 year after baseline examinations. RESULTS: Eighty patients completed the first crossover period and 75 completed the full 1 year of follow-up. Active pacing induced significant quality of life improvements, in the order of 9-44%, regardless of programming sequence. Discontinuation of pacing after a first active period resulted in the return of symptoms. Fourteen patients requested early reprogramming after having been programmed to inactive pacing after a first period of active pacing. Seventy-six patients preferred active pacing after the crossover period. A further 6 months of pacing induced progressive improvement in symptoms already favourably influenced. CONCLUSION: Atrioventricular synchronous pacing has a profound beneficial effect on most domains of quality of life in patients with hypertrophic obstructive cardiomyopathy refractory to drug treatment.

Adult↗
PubMed1998

Modification of atrioventricular conduction as adjunct therapy for pacemaker-treated patients with hypertrophic obstructive cardiomyopathy.

AIMS: Atrioventricular synchronous pacing offers symptomatic relief for patients with drug-refractory hypertrophic obstructive cardiomyopathy. Successful treatment requires complete right ventricular apical pre-excitation. Enhanced atrioventricular conduction renders this difficult in some patients. The aim of this study was to evaluate whether selective prolongation of atrioventricular conduction is a useful tool for optimization of treatment in patients with hypertrophic obstructive cardiomyopathy primarily refractory to cardiac pacing. METHODS: Six patients refractory to pacemaker treatment for 3-19 months underwent radiofrequency modification of atrioventricular conduction. Patients were followed with echo-Doppler, exercise testing and clinical evaluation for 6-12 months after modification. RESULTS: Intrinsic PQ time was significantly prolonged from 175 +/- 18 ms to 253 +/- 22 ms; however, one patient exhibited complete block at one month follow-up. Left ventricular outflow tract obstruction decreased from 74 +/- 17 mmHg to 28 +/- 27 mmHg at the 6-month follow-up. Symptomatic improvement of at least one functional class was recorded in all patients; exercise tolerance remained unchanged, however, less angina and dyspnoea were reported in everyday life. CONCLUSION: Radiofrequency modification of atrioventricular conduction, with persistent prolongation of the PQ interval, enhances the effects of pacing in patients with hypertrophic obstructive cardiomyopathy. This treatment enhances left ventricular outflow tract gradient reduction and improves symptoms.

Adult↗
PubMed1997

Incidence of sudden death after radiofrequency ablation of the atrioventricular junction for atrial fibrillation.

This study assesses the incidence of sudden death and classifies the causes of death following radiofrequency ablation of the atrioventricular (AV) junction. We studied 220 patients with paroxysmal (n = 105) or chronic (n = 115) atrial fibrillation (AF) and a mean age of 64 +/- 12 years. These patients were followed 31 +/- 15 months after radiofrequency ablation of the AV junction and pacemaker implantation. In 86 patients, structural heart disease was identified before the procedure. All patients were traced via the Swedish National Civic Registry and Cause of Death Registry. The cause-of-death was classified according to data from death certificates, autopsy protocols, and medical records. Thirty-one patients (mean age 69 +/- 11 years, 16 men) died 15 +/- 15 months (range 0.2 to 60) after the procedure. There were 6 sudden unexplained deaths, 14 cardiovascular deaths, and 11 deaths from noncardiovascular causes. Eleven patients, all with structural heart disease, died suddenly out of hospital 16 +/- 16 months (range 0.2 to 42) after the procedure. In 6 of these there was no obvious cause of death. Three of these 6 patients underwent autopsy, which showed extensive coronary artery disease (n = 1), severe heart failure (n = 1) and cardiac hypertrophy and dilation (n = 1). The remaining 3 all had depressed left ventricular systolic function and a history of congestive heart failure. Five of the patients who died suddenly from cardiovascular causes had autopsies that revealed acute myocardial infarction (n = 4) and massive pulmonary embolism (n = 1).

Aged↗
PubMed1997

Activators of protein kinase A induce a glibenclamide-sensitive 86Rb+ efflux in rat isolated aorta.

The effect of activators of protein kinase A on membrane K+ permeability and the interaction of these compounds with cromakalim, an opener of ATP-sensitive K+ channels (K(ATP) channels), were investigated. Membrane K+ permeability was assessed by measuring 86Rb+ efflux from rings of rat aorta. Forskolin, an activator of adenylate cyclase, and isobutylmethylxanthine (IBMX), a nonselective phosphodiesterase inhibitor, induced small, concentration-dependent increases in tracer efflux up to 20-40% over the basal level. The effect of forskolin was abolished by the K+ channel blocker tedisamil (1 microM) and partially inhibited by glibenclamide (1 microM), a relatively selective blocker of K(ATP) channels. Further studies were conducted in the presence of 35 mM KCI in the bath in order to increase the size of the 86Rb+ efflux stimulated by forskolin and IBMX. At high concentrations, these compounds produced a biphasic effect with a peak increase being followed by a lower plateau value. Glibenclamide inhibited the 86Rb+ efflux response to forskolin and IBMX by 50-80%. The K+ channel blockers tedisamil (1 microM), Ba2+ (1 mM) and tetraethylammonium (10 mM) also reduced the peak response to forskolin by about 50% and abolished or greatly inhibited the plateau response. In addition to the small effect on basal 86Rb+ efflux, forskolin (0.3 microM) increased cromakalim-induced 86Rb+ efflux 3.4 times. At higher concentrations, however, a concentration-dependent inhibition was observed with an IC50 value of 7.6 +/- 0.4 microM. 1,9-dideoxyforskolin, which does not increase cAMP, increased neither basal nor cromakalim-induced 86Rb+ efflux; however, it inhibited cromakalim-stimulated tracer efflux with an IC50 value of 22 +/- 2 microM. It is concluded that forskolin and IBMX, probably by increasing intracellular cAMP levels, induce a 86Rb+ efflux from rat aorta, the major part of which is glibenclamide-sensitive and may pass through K(ATP) channels. In addition, low concentrations of forskolin greatly facilitate the K(ATP) channel opening effect of cromakalim whereas high concentrations block the channel; this blocking effect of forskolin is unrelated to the cAMP elevating action.

Animals↗
PubMed1997

Inhibition by protein kinase C of the 86Rb+ efflux and vasorelaxation induced by P1075, a K(ATP) channel opener, in rat isolated aorta.

In rat aortic rings, P1075, an opener of ATP-dependent potassium channels (K(ATP) channels), produces relaxation and 86Rb+ efflux from preloaded tissues; the increase in 86Rb+ efflux qualitatively reflects K(ATP) channel opening. In this study we have investigated the effects of protein kinase C modulation on the 86Rb+ efflux stimulating, the vasorelaxant and the binding properties of P1075. Phorbol 12,13-dibutyrate (PDBu), a direct activator of protein kinase C, inhibited the 86Rb+ efflux produced by P1075 with an IC50 value of 20+/-2 nM. Phorbol 12-myristate 13-acetate (PMA), another stimulator of protein kinase C, was 150 times weaker in this respect whereas 4alpha-PDBu, the inactive stereoisomer of PDBu, was ineffective. Staurosporine (300 nM), an inhibitor of protein kinase C, induced a small but significant increase of P1075-induced tracer efflux and partially reversed the inhibitory effect of PDBu on P1075-stimulated tracer efflux. The vasorelaxant effect of P1075 was inhibited only to a moderate degree by PDBu at concentrations which inhibited P1075-induced 86Rb+ efflux to >90%; however, in the presence of PDBu, the relaxation kinetics of P1075 were increasingly slowed. The vasorelaxant effect of P1075 in the presence of PDBu was still sensitive to inhibition by glibenclamide (100 nM), the standard inhibitor of the K(ATP) channel openers. Specific binding of [3H]-P1075 to rat aortic rings was unaffected by PDBu and PMA even in the micromolar concentration range. The data show that stimulation of protein kinase C inhibits the K+ channel opening effect of P1075 in rat aorta and suggest that protein kinase C may exert a weak tonic inhibition on the K(ATP) channels in this vessel under quasiphysiological conditions. At concentrations of PDBu which essentially abolished P1075-induced tracer efflux, the glibenclamide-sensitive vasorelaxant effect of P1075 was slowed down but not prevented; this supports earlier suggestions that K+ channel openers are also able to relax smooth muscle cells by a mechanism independent of K(ATP) channel opening.

Adenosine Triphosphate↗
PubMed1997

Interaction between thiol-modifying agents and P1075, a K(ATP) channel opener, in rat isolated aorta.

In vascular smooth muscle, openers of ATP-dependent potassium channels (K(ATP) channels), such as P1075 (N-cyano-N'-(1,1-dimethylpropyl)-N"-3-pyridylguanidine), produce relaxation. In this study we have investigated the effects of thiol-modifying agents on the binding of P1075 and on the 86Rb+ efflux stimulating and vasorelaxant effects of the opener in rat aortic rings. The increase in 86Rb+ efflux induced by P1075 was taken as a qualitative measure of K+ channel opening. The hydrophilic SH-group-oxidizing substance, thimerosal (1 to 100 microM), abolished specific binding of [3H]-P1075 with an IC50 value of 7.6+/-1.2 microM; at 30 microM, the half time for inhibition was 38 min. Two other thioloxidizing agents, PMB (4-hydroxy-mercuribenzoic acid) and DTBNP (2,2'-dithio-bis(5-nitropyridine)), inhibited binding up to 86% and 44%, respectively. The disulphide bond reducing substance, DTT (1,4-dithiothreitol, 0.1 to 1 mM), reduced [3H]-P1075 binding by up to 20% and partially reversed the inhibitory effect of thimerosal. In 86Rb+ efflux experiments, thimerosal (3 to 100 microM) concentration-dependently increased basal efflux but inhibited P1075-stimulated tracer efflux with an IC50 value of 7+/-1 microM. The inhibitory effect occurred with a half-time of approximately 8 min and was essentially reversed by DTT. In rings precontracted with noradrenaline, thimerosal inhibited the vasorelaxant effect in a noncompetitive manner, shifting the concentration-relaxation curves to the right and reducing maximum relaxation. The data show that oxidation of thiol groups interferes with the binding of the K(ATP) channel opener, P1075; concomitantly, the 86Rb+ efflux stimulating and the vasorelaxant effects are inhibited. Reduction of disulphide bonds by DTT has only minor effects on the action of P1075. Collectively, the results suggest that intact thiol groups are essential for the functioning of the K(ATP) channel in rat aorta. The different kinetics governing the inhibition of opener binding and of opener-stimulated 86Rb+ efflux suggest that the SH-groups involved in the two processes differ in their accessibility to thimerosal and/or in their reactivity.

Animals↗
PubMed1997

Long-term effects of dual chamber pacing in patients with hypertrophic cardiomyopathy without outflow tract obstruction at rest.

BACKGROUND: Atrioventricular-synchronous pacing is beneficial in patients with hypertrophic obstructive cardiomyopathy. The effects of pacing in patients without significant left ventricular outflow tract obstruction at rest are, however, less well explored. This study compares the long-term outcome of pacing patients with and without significant left ventricular outflow tract obstruction at rest. METHODS: Forty-one patients with hypertrophic obstructive cardiomyopathy were studied, 19 with a left ventricular outflow tract gradient < 40 mmHg at rest, but exceeding 50 mmHg during provocation with isoproterenol (group A), and 22 with a left ventricular outflow tract obstruction > 40 mmHg at rest (group B). Before the implantation of a permanent pacemaker, the patients were studied according to a temporary pacing protocol. This included graded isoproterenol provocation of the left ventricular outflow tract obstruction, which was assessed by echo Doppler. Following permanent pacemaker implantation, the patients were regularly followed up with echo Doppler, exercise testing and monitoring of the clinical condition. RESULTS: Isoproterenol provocation was reproducible and the technique did not cause any clinically important side effects. Left ventricular outflow tract gradient reduction after chronic pacing did not differ between the two groups. In group A, it decreased from 98 +/- 30 mmHg in sinus rhythm to 42 +/- 26 mmHg during pacing. The corresponding values in group B were 87 +/- 40 mmHg to 36 +/- 24 mmHg. The clinical condition improved similarly in the two groups. Exercise capacity increased significantly and perceived dyspnoea and angina pectoris were significantly lower at submaximal levels of exercise after 6 months of pacing. CONCLUSION: Hypertrophic obstructive cardiomyopathy patients who only exhibit significant left ventricular outflow tract obstruction during provocation benefit as much from pacemaker treatment as do patients who already have significant obstruction at rest. Isoproterenol is a safe and reproducible method for pre-pacing evaluation of hypertrophic obstructive cardiomyopathy patients.

Adult↗
PubMed1997

Pacing in hypertrophic obstructive cardiomyopathy. A randomized crossover study. PIC Study Group.

BACKGROUND: Uncontrolled studies have shown that short atrioventricular delay dual chamber pacing reduces outflow tract obstruction in hypertrophic obstructive cardiomyopathy. Although the exact mechanism of this beneficial effect is unclear, this seems a promising potential new treatment for hypertrophic obstructive cardiomyopathy. METHOD: In order to evaluate the impact of pacing therapy, were performed a randomized multicentre double-blind cross-over (pacemaker activated vs non activated) study to investigate modification of echocardiography, exercise tolerance, angina, dyspnoea and quality of life in 83 patients with a mean age of 53 (range 22-87) years with symptoms refractory or intolerant to classical drug treatment. RESULTS: After 12 weeks of activated or inactivated pacing, independent of which phase was first, the pressure gradient fell from 59 +/- 36 mmHg to 30 +/- 25 mmHg (P < 0.001) with active pacing. Exercise tolerance improved by 21% in those patients who at baseline tolerated less than 10 min of Bruce protocol; symptoms of dyspnoea and angina also improved significantly from NYHA class 2.4 to 1.4 and 1.0 to 0.4, respectively (P < 0.007). Quality of life assessment with a validated questionnaire objectivated the subjective improvement. CONCLUSION: Pacemaker therapy is of clinical and haemodynamic benefit for patients with hypertrophic obstructive cardiomyopathy, left ventricular outflow gradient at rest over 30 mmHg who are symptomatic despite drug treatment.

Adult↗
PubMed1996

Influence of right ventricular pacing site on left ventricular outflow tract obstruction in patients with hypertrophic obstructive cardiomyopathy.

OBJECTIVES: This study was designed to show the influence of right ventricular pacing site on left ventricular outflow tract obstruction during pacing treatment of patients with hypertrophic obstructive cardiomyopathy. BACKGROUND: Atrioventricular synchronous pacing has been reported to reduce left ventricular outflow obstruction and symptoms in patients with hypertrophic obstructive cardiomyopathy. A paradoxic septal movement induced by right ventricular pacing has been implicated as the mechanism behind the reduced left ventricular outflow tract obstruction; however, the importance of pacing site has not been clarified. METHODS: Cardiac output, measured invasively, and left ventricular outflow tract gradient, estimated by Doppler echocardiography, were studied in 15 patients with hypertrophic obstructive cardiomyopathy. Measurements were made with the right ventricular electrode in the septal and apical positions during temporary pacing and during sinus rhythm. RESULTS: Right ventricular apical pacing reduced the outflow tract gradient in all 15 patients to a mean +/- SD of 38 +/- 24 mm Hg from 96 +/- 33 mm Hg during sinus rhythm. During high septal pacing the outflow tract gradient was not reduced, remaining at 93 +/- 44 mm Hg. No significant changes in cardiac output were seen when levels during sinus rhythm (6.4 liters/min), apical pacing (6.4 liters/min) and high septal pacing (5.6 liters/min) were compared. CONCLUSIONS: The right ventricular pacing site is of crucial importance for reducing left ventricular outflow tract obstruction when patients with hypertrophic obstructive cardiomyopathy are treated with pacing. Cardiac output is not reduced by apical pacing.

Adult↗
PubMed1995

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.

Adult↗