Knut Gjesdal

Resting heart rate and physical activity as risk factors for lone atrial fibrillation: a prospective study of 309 540 men and women

Objective To study the impact of resting heart rate and leisure time physical activity at middle age on long term risk of drug treated lone atrial fibrillation (AF). Design Longitudinal cohort study of 309 540 Norwegian men and women aged 40–45 years examined during 1985–1999 followed from 2005 through 2009. Setting Data from a national health screening programme were linked to the Norwegian Prescription Database (NorPD). Patients The cohort comprised 162 078 women and 147 462 men; 575 (0.4%) men and 288 women (0.2%) received flecainide and 568 men and 256 women sotalol and were defined as patients with AF. Interventions No interventions. Main outcome measures The outcome was lone fibrillation defined by having at least one prescription of flecainide or sotalol registered in NorPD between 2005 and 2009. Cox proportional hazard regression models were used to assess time to first prescription. Results The risk for being prescribed these drugs increased with decreasing baseline resting heart. Adjusted hazard ratio (HR) per 10 beats/min decrease in resting heart rate for flecainide prescription was 1.26 in men (95% CI 1.17 to 1.35) and 1.15 (95% CI 1.05 to 1.27) in women. Similar effects were seen for sotalol in men, but not in women. Men who reported intensive physical activity were more often prescribed flecainide than those in the sedentary group (adjusted HR=3.14, 95% CI 2.17 to 4.54). Conclusions This population based study supports the hypothesis that the risk of drug treated lone AF increases with declining resting heart rate in both sexes, and with increasing levels of self-reported physical activity in men.

Increased uptake of transdermal glyceryl trinitrate during physical exercise and during high ambient temperature

In a study of GTN absorption during exercise and high ambient temperature, 12 healthy volunteers carried 10 mg glyceryl trinitrate (GTN, nitroglycerin) transdermal patches for 6 hours during each of 3 days. During a control day the mean plasma GTN concentration ranged from 1.0 nmol/L (SD +/- 0.8 nmol/L) to 1.5 nmol/L (SD +/- 1.0 nmol/L), whereas during a bicycle ergometer day mean GTN concentration was increased to 3.1 nmol/L (SD +/- 1.7 nmol/L, p less than 0.001). During a sauna day volunteers stayed for 20 minutes in a sauna, and mean GTN concentration in plasma rose to 7.3 nmol/L (SD +/- 1.7 nmol/L, p less than 0.001). Systolic blood pressure increased during exercise (p less than 0.01) but decreased significantly in the sauna (p less than 0.01). Headache was noted frequently (9 of 12 subjects) and dizziness by a few (3 of 12). The demonstrated increased transdermal absorption in our study may infer an increased effect during workload. Whereas the increase in transdermally absorbed GTN may be beneficial to the exercising angina patient, increased effects of GTN may be undesirable in hot surroundings. A study on angina patients is justified to assess whether this phenomenon bears clinical relevance.

Molecular genetic analysis of long QT syndrome in Norway indicating a high prevalence of heterozygous mutation carriers

Mutations in the KCNQ1, HERG, SCN5A, minK and MiRP1 genes cause long QT syndrome (LQTS), of which there are two forms: the Romano Ward syndrome and the Jervell and Lange‐Nielsen syndrome. We have performed DNA sequencing of the LQTS‐associated genes in 169 unrelated patients referred for genetic testing with respect to Romano Ward syndrome and in 13 unrelated patients referred for genetic testing with respect to Jervell and Lange‐Nielsen syndrome. A total of 37 different mutations in the 5 genes, of which 20 were novel, were identified. Among patients with the most stringent clinical criteria of Romano Ward syndrome, a mutation was identified in 71 %. Twelve of the 13 unrelated patients referred for genetic testing with respect to Jervell and Lange‐Nielsen syndrome were provided with a molecular genetic diagnosis. Cascade genetic screening of 505 relatives of index patients with molecularly defined LQTS identified 251 mutation carriers. The observed penetrance was 41 %. Although caution must be exerted, the prevalence of heterozygotes for mutations in the LQTS‐associated genes in Norway could be in the range 1/100–1/300, based on the prevalence of patients with Jervell and Lange‐Nielsen syndrome.

Effect of exercise training in patients with heart failure: a pilot study on autonomic balance assessed by heart rate variability.

Background Heart rate variability (HRV) is decreased in patients with congestive heart failure (CHF) and is a prognostic marker in this disease. Exercise training is now regarded as an important part of the treatment of patients with CHF, but the effect on HRV and the association between this effect and the effect on neurohormones are not well assessed. Methods Heart rate recording was performed in 12 patients with CHF (mean age 67 ± 8 years) with CHF NYHA functional class III, before and after 12 weeks of exercise training. The association with exercise capacity and serum levels of atrial natriuretic peptide was assessed. We also evaluated the correlation between HRV and survival at follow-up 87 months later. Results At baseline there was a significant correlation between mean heart rate and work performed during max cycle test (r=0.650, P=0.022) and the HRV parameter standard deviation normal to normal (SDNN) (r=0.678, P=0.015). After exercise training there was a significant increase in work performed (30.3 ± 14.2 versus 38.1 ± 14.1 kJ), 6-min walk test (502 ± 88 versus 552 ± 59 m, P=0.006) and SDNN (117.3 ± 40.7 versus 128.6 ± 42.3 ms, P=0.028). At 87 months of follow-up, there was a borderline significant difference between survivors and non-survivors. Only the survivors had a significant increase in SDNN after exercise training. Conclusion This pilot study demonstrates an improvement with regard to parameters for HRV after exercise training in patients with CHF. The study suggests that the positive effect of exercise training in patients with CHF involves an attenuation of the reduced HRV response, and that this improvement might have prognostic significance. Eur J Cardiovasc Prevention Rehab 11:162–167

The activation of platelet function, coagulation, and fibrinolysis during radiofrequency catheter ablation in heparinized patients.

Hemostatic Activation during RF Ablation. Introduction: Catheter ablation may be complicated by clinical thromboembolism in about 1% of patients.

Heating and cooling of the nitroglycerin patch application area modify the plasma level of nitroglycerin

Summary19 healthy volunteers wore a nitroglycerin patch releasing 10 mg per 24 h for 2 h. Subsequently, the skin area surrounding the patch was exposed to 15 min of local heating with an infrared bulb (Group A, n =10), or local cooling with an ice-pack (Group B, n = 9). The patch was protected by an insulating shield (Styrofoam).After 10 min of heating, the median (Walsh) plasma nitroglycerin level increased from 3.1 to 7.6 nmol·1−1. Body temperature remained constant. After 15 min of cooling the median plasma level had dropped from 2.1 to 1.4 nmol·1−1.The results demonstrate that changes in skin temperature may cause extensive short-term changes in the bioavailability of nitroglycerin. Presumably, a subcutaneous or cutaneous reservoir builds up during transdermal treatment, and changes in regional cutaneous blood flow affect the rate of drainage from the reservoir into the systemic circulation.

Digitalis: a dangerous drug in atrial fibrillation? An analysis of the SPORTIF III and V data

Objective: In heart failure, digitalis increases exercise capacity and reduces morbidity, but has no effect on survival. This raises the suspicion that the inotropic benefits of digitalis may be counteracted by serious adverse effects. Patients with atrial fibrillation (AF) were studied to clarify this. Design: In the Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation (SPORTIF) III and V studies, 7329 patients with AF at moderate-to-high risk were randomised to preventive treatment of thromboembolism, either with warfarin or the oral direct thrombin inhibitor ximelagatran. The survival of users and non-users of digitalis was investigated. Results: At baseline, 53.4% of the study population used digitalis, and these patients had a higher mortality than non-users (255/3911 (6.5%) vs 141/3418 (4.1%), p<0.001; hazard ratio (HR) = 1.58 (95% CI 1.29 to 1.94)). Digitalis users also had more baseline risk factors. After multivariate risk factor adjustment, the increased mortality persisted (p<0.001; HR = 1.53 (95% CI 1.22 to 1.92 vs 1.23 to 1.92)). Conclusions: The results suggest that digitalis, like other inotropic drugs, may increase mortality. This may be concealed in heart failure, but be revealed in patients with AF, who need the rate-reducing effect of digitalis, but do not benefit much from an increased inotropy. Cautious interpretation of the data is mandatory since the patients were not randomised with respect to digitalis use.

Increased platelet and vascular smooth muscle reactivity to low-dose adrenaline infusion in mild essential hypertension

During low-dose adrenaline infusion, platelet count, platelet size, plasma beta-thromboglobulin (BTG) and forearm vascular resistance (FVR) were measured in twelve 40-year-old men with mild, untreated hypertension. The average platelet count increased from 195 to 226 X 10(9)/l (P less than 0.001), platelet size from 7.31 to 7.53 X 10(-15)/l (P less than 0.01), BTG from 0.61 to 1.08 nmol/l (P less than 0.02) and FVR decreased from 97 to 58 (arbitrary units; P less than 0.001) during the infusion. The change in platelet count reflects splenic release of platelets, the change in plasma BTG reflects platelet release reaction, while the reduced FVR reflects vascular smooth muscle cell relaxation. In 11 normotensive men aged 40 years, platelet count increased from 187 to 201 X 10 g/l (P less than 0.01) during an equal low-dose adrenaline infusion. This increase in platelet count is significantly less than in the hypertensive group (P less than 0.01). There was statistically no significant change in platelet size, BTG or FVR in the normotensive group. Arterial adrenaline rose from 0.5 to 2.5 nmol/l in the hypertensive and from 0.5 to 2.4 nmol/l in the normotensive group. A third group of 12 normotensive men received saline infusion: neither platelet parameters nor FVR changed in this group. Thus, a small and equal dose of adrenaline elicited a greater increase in platelet count, an enhanced platelet release reaction and a more pronounced forearm vasodilation in hypertensive than in normotensive subjects.

Increased Platelet Size and Release Reaction in Essential Hypertension

Basal platelet function was measured in 35 40-year-old men with untreated mild essential hypertension and compared with 44 age-matched normotensive men. The groups differed significantly with respect to platelet size in venous blood (hypertensive, 7.46 ± 0.10 x 10-15 I versus normotensive, 7.11 ± 0.09 x 10-15 I; P = 0.01) and arterial concentration of the platelet-specific protein β-thromboglobulin (hypertensive, 1.11 ± 0.23 nmol/l versus normotensive, 0.59 ± 0.04 nmol/l; P = 0.02). The normotensive subjects had significantly higher β-thromboglobulin (BTG) in venous than in arterial blood (P < 0.01). The hypertensive men showed no such difference. In contrast to the normotensive subjects, the hypertensive group had reduced arterial compared with venous platelet count (P < 0.01). This may reflect an increased liability in the hypertensive subjects to lose platelets through adherence to the cannula during arterial blood sampling. The above findings point to increased platelet activity in essential hypertension, particularly in arterial blood.

Consensus document on antithrombotic therapy in the setting of electrophysiological procedures

Guidelines and Expert Consensus documents are proposed to help physicians to select the best possible diagnostic or therapeutic strategies for an individual patient with a specific disease. Recommendations issued from these documents are based on an extensive review of the literature and on discussions among experts when hard data are incomplete or missing. It has been shown that patient outcomes improve when guidelines recommendations are applied in clinical practice. Publication and promotion of these guidelines is one of the most important tasks of scientific societies. The recently created European Heart Rhythm Association (EHRA) wants to meet this commitment in its specific field of competence and one assignment of the scientific committee of EHRA is to propose and promote Guidelines in the management of heart rhythm disturbances not already covered by the European Society of Cardiology (ESC). Electrophysiological studies (EPSs), whether or not associated with therapeutic procedures (ablation using different sources of energy or reduction of tachycardia), show the percutaneous introduction of one or multiple catheters to record the electrical activity of the heart or to pace its different cavities. The introduction and manipulation of these catheters in arteries, veins, or cardiac cavities have multiple pathophysiological consequences and one of the most evident is to activate the coagulation cascade with the risk to induce new clots or to mobilize pre-existing ones. Furthermore, withdrawal of catheters induces haemorrhage usually limited by the compression of the site of venous or arterial puncture. There is also a close relationship between EPS and thrombus formation (thrombogenesis) and thus, rhythmologists need to balance the risks between thrombo-embolism and bleeding. There are no guidelines on the use of antithrombotic therapies in the setting (before, during, and after) of EPS. Generally, different laboratories have their own approaches to this clinical problem. The aim of the present document is …