Importance of beta-blocker dose in prevention of ventricular tachyarrhythmias, heart failure hospitalizations, and death in primary prevention implantable cardioverter-defibrillator recipients: a Danish nationwide cohort study.

Aims: There is a paucity of studies investigating a dose-dependent association between beta-blocker therapy and risk of outcome. In a nationwide cohort of primary prevention implantable cardioverter-defibrillator (ICD) patients, we aimed to investigate the dose-dependent association between beta-blocker therapy and risk of ventricular tachyarrhythmias (VT/VF), heart failure (HF) hospitalizations, and death. Methods and results: Information on ICD implantation, endpoints, comorbidities, beta-blocker usage, type, and dose were obtained through Danish nationwide registers. The two major beta-blockers carvedilol and metoprolol were examined in three dose levels; low (metoprolol ≤ 25 mg; carvedilol ≤ 12.5 mg), intermediate (metoprolol 26-199 mg; carvedilol 12.6-49.9 mg), and high (metoprolol ≥ 200 mg; carvedilol ≥ 50 mg). Time to events was investigated utilizing multivariate Cox models with beta-blocker as a time-dependent variable. From 2007 to 2012, 2935 first-time ICD devices were implanted. During follow-up, 399 patients experienced VT/VF, 728 HF hospitalizations and 361 died. As compared with patients not on beta-blockers, low, intermediate, and high dose had significantly reduced risk of HF hospitalizations {hazard ratio (HR) = 0.68 [0.54-0.87], P = 0.002; HR = 0.53 [0.42-0.66], P < 0.001; HR = 0.43 [0.34-0.54], P < 0.001} and death (HR = 0.47 [0.35-0.64], P < 0.001; HR = 0.29 [0.22-0.39], P = 0.001; HR = 0.24 [0.18-0.33], P < 0.001). For the endpoint of VT/VF, only intermediate and high dose beta-blocker was associated with significantly reduced risk (HR = 0.58 [0.43-0.79], P < 0.001; HR = 0.53 [0.39-0.72], P < 0.001). No significant difference was found between comparable doses of carvedilol and metoprolol on any endpoint (P = 0.06-0.94). Conclusion: In primary prevention ICD patients, beta-blocker therapy was associated with significantly reduced risk of all endpoints, as compared with patients not on beta-blocker, with the suggestion of a dose-dependent effect. No detectable difference was found between comparable doses of carvedilol and metoprolol.

Genetic analysis of an ephemeral intraspecific hybrid zone in the hypervariable tree, Metrosideros polymorpha, on Hawai'i Island.

Intraspecific hybrid zones involving long-lived woody species are rare and can provide insights into the genetic basis of early-diverging traits in speciation. Within the landscape-dominant Hawaiian tree, Metrosideros polymorpha, are morphologically distinct successional varieties, incana and glaberrima, that dominate new and old lava flows, respectively, below 1200 me on volcanically active Hawai'i Island, with var. glaberrima also extending to higher elevations and bogs. Here, we use morphological measurements on 86 adult trees to document the presence of an incana-glaberrima hybrid zone on the 1855 Mauna Loa lava flow on east Hawai'i Island and parent-offspring analysis of 1311 greenhouse seedlings from 71 crosses involving 72 adults to estimate heritabilities and genetic correlations among vegetative traits. Both the variation in adult leaf pubescence at the site and the consistency between adult and offspring phenotypes suggest the presence of two hybrid classes, F1s and var. incana backcrosses, as would be expected on a relatively young lava flow. Nine nuclear microsatellite loci failed to distinguish parental and hybrid genotypes. All four leaf traits examined showed an additive genetic basis with moderate to strong heritabilities, and genetic correlations were stronger for the more range-restricted var. incana. The differences between varieties in trait values, heritabilities and genetic correlations, coupled with high genetic variation within but low genetic variation between varieties, are consistent with a multi-million-year history of alternating periods of disruptive selection in contrasting environments and admixture in ephemeral hybrid zones. Finally, the contrasting genetic architectures suggest different evolutionary trajectories of leaf traits in these forms.

Incipient radiation within the dominant Hawaiian tree Metrosideros polymorpha.

Although trees comprise a primary component of terrestrial species richness, the drivers and temporal scale of divergence in trees remain poorly understood. We examined the landscape-dominant tree, Metrosideros polymorpha, for variation at nine microsatellite loci across 23 populations on young Hawai'i Island, sampling each of the island's five varieties throughout its full geographic range. For four varieties, principal coordinate analysis revealed strong clustering of populations by variety across the 10 430 km(2) island, indicating partitioning of the species into multiple evolutionarily significant units. The single island-endemic form, riparian var. newellii, showed especially strong differentiation from other varieties despite occurring in sympatry with other varieties and likely evolved from a bog form on the oldest volcano, Kohala, within the past 500 000 years. Along with comparable riparian forms on other Pacific Islands, var. newellii appears to represent parallel incipient ecological speciation within Metrosideros. Greater genetic distance among the more common varieties on the oldest volcano and an inverse relationship between allelic diversity and substrate age appear consistent with colonization of Hawai'i Island by older, partially diverged varieties followed by increased hybridization among varieties on younger volcanoes. This study demonstrates that broad population-level sampling is required to uncover patterns of diversification within a ubiquitous and long-lived tree species. Hawaiian Metrosideros appears to be a case of incipient radiation in trees and thus should be useful for studies of divergence and the evolution of reproductive isolating barriers at the early stages of speciation.

Systemic nitric oxide clamping in normal humans guided by total peripheral resistance.

AIM: We wanted to stabilize the availability of nitric oxide (NO) at levels compatible with normal systemic haemodynamics to provide a model for studies of complex regulations in the absence of changes in NO levels. METHODS: Normal volunteers (23-28 years) were infused i.v. with the nitric oxide synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) at 0.5 mg kg(-1) h(-1). One hour later, the NO donor sodium nitroprusside (SNP) was co-infused in doses eliminating the haemodynamic effects of l-NAME. Haemodynamic measurements included blood pressure (MABP) and cardiac output (CO) by impedance cardiography. RESULTS: l-NAME increased MABP and total peripheral resistance (TPR, 1.02 + or - 0.05 to 1.36 + or - 0.07 mmHg s mL(-1), mean + or - SEM, P < 0.001). With SNP, TPR fell to a stable value slightly below control (0.92 + or - 0.05 mmHg s mL(-1), P < 0.05). CO decreased with l-NAME (5.8 + or - 0.3 to 4.7 + or - 0.3 L min(-1), P < 0.01) and returned to control when SNP was added (6.0 + or - 0.3 L min(-1)). A decrease in plasma noradrenaline (42%, P < 0.01) during l-NAME administration was completely reversed by SNP. Plasma renin activity decreased during l-NAME administration and returned towards normal after addition of SNP. In contrast, plasma aldosterone was increased by l-NAME and remained elevated. CONCLUSIONS: Concomitant NOS inhibition and NO donor administration can be adjusted to maintain TPR at control level for hours. This approach may be useful in protocols in which stabilization of the peripheral supply of NO is required. However, the dissociation between renin and aldosterone secretion needs further investigation.

Clinical experience of a new rate drop response algorithm in the treatment of vasovagal and carotid sinus syncope.

Dual chamber pacing has proven beneficial in patients with sudden drops in heart rate as seen in vasovagal syncope and carotid sinus syndrome. Newer algorithms for faster detection of an insidious drop in heart rate and short lasting intervention pacing at a high rate, as in the rate drop response algorithm in the Medtronic Kappa series of pacemakers, might improve the effect of pacing. Two case reports, that demonstrate the use of these rate drop response algorithms, are presented. A 24-year-old woman with recurrent episodes of syncope and repeated tilt-table tests with vasovagal cardioinhibitory outcomes had a Medtronic Kappa 400 pacemaker implanted. Syncope was abolished during repeat tilt-table testing following pacemaker implantation and proper functioning of the rate drop response algorithm. The patient has been free of syncope during follow-up apart from a single episode that occurred due to neglect of vasovagal warning symptoms. A 52-year-old man with coronary artery disease developed recurrent blackouts. Carotid sinus massage resulted in 5.5 s of asystole and presyncope. A Medtronic Kappa 700 pacemaker with a rate drop response algorithm was implanted and the patient became asymptomatic. The rate drop response algorithm is discussed in detail based upon the case reports, and recommendations are given for the use of this algorithm in patients with vasovagal syncope and carotid sinus syndrome.

Efficacy and safety of intravenously administered dofetilide in acute termination of atrial fibrillation and flutter: a multicenter, randomized, double-blind, placebo-controlled trial. Danish Dofetilide in Atrial Fibrillation and Flutter Study Group.

BACKGROUND: This study was designed to assess the efficacy and safety of intravenous dofetilide in acute termination of atrial fibrillation (AF) and flutter (AFL). Dofetilide, an investigational class III antiarrhythmic agent, selectively inhibits the rapid component of the delayed rectifier potassium current, thus prolonging the effective refractory period and duration of the action potential. Dofetilide can be administered intravenously and has a rapid onset of electrophysiologic action. METHODS AND RESULTS: Ninety-six patients with AF (n = 79) or AFL (n = 17) with a median arrhythmia duration of 62 days (range 1 to 180) were randomized to placebo (n = 30) or 8 micrograms/kg IV dofetilide (n = 66) over 30 minutes. Conversion was defined as termination of the atrial arrhythmia within 3 hours from the start of infusion. The conversion rate was 30.3% after dofetilide and 3.3% after placebo (P <.006). Conversion rate was higher in AFL than in AF: 64% versus 24% (P =. 012). In nonconverters, there was no statistically significant difference between the change in heart rate among the dofetilide-treated compared with the placebo-treated patients (P =. 42). Torsade de pointes ventricular tachycardia developed in 2 patients (3%). In both patients, drug infusion was discontinued before the event because of prolongation of the QT interval. CONCLUSIONS: Intravenous dofetilide is effective in acute termination of AF and AFL of medium duration, with a particularly high efficacy rate in AFL. A small but serious risk of proarrhythmia must be anticipated.

Correlation between serial changes in left-sided heart chambers and atrial natriuretic peptide and N-terminal pro atrial natriuretic peptide after a first myocardial infarction. An echocardiographic study.

Dilatation of the left ventricle predicts morbidity and mortality after acute myocardial infarction. We compared serial echocardiographic examinations of the left atrium and ventricle with measurements of plasma atrial natriuretic peptide (ANP) and plasma N-terminal pro atrial natriuretic peptide (NT-proANP) in 22 patients during the first 6 months following a first myocardial infarction. ANP, but not NT-proANP, was found to be significantly correlated to the diastolic/systolic size of the left atrium (r = 0.58/0.60) and the systolic size of the left ventricle (r = 0.43) in the acute phase 2-4 days after infarction. At 10-12 days after the infarction, we found a significant correlation between all sizes of the left-sided chambers and ANP, whereas NT-proANP only correlated with the left atrial sizes. Three months after the infarction, all sizes of the left-sided chambers correlated with both ANP and NT-proANP, with the exception of a non-significant correlation between NT-proANP and the left atrial diastolic size. After 6 months only the area of the diastolic and systolic left atrium correlated with plasma ANP and only the systolic size of the left atrium correlated with NT-proANP. The percentage change in the size of the left atrium, but not the left ventricle, correlated significantly with the percentage change in both ANP (r = 0.57) and NT-proANP (r = 0.70). We conclude that the distension of the left atrium rather than the dilatation of the left ventricle is related to the concentration of ANP and NT-proANP after an acute myocardial infarction.

[Acute arsenic poisoning]. / Akut arsenforgiftning.

We report three cases of arsenic poisoning in a chemical factory. Three workers were exposed to vinyzene 10,10'-oxydephenarsine and developed mild symptoms of acute poisoning. All patients were treated with dimercaprol, and recovered after a few days. Urine analysis did not show increased arsenic excretion, but this could be due to the large urine samples taken. It is recommended that a urine sample is taken right after admission to hospital and new samples after eight and 16 hours.

Treatment of anomalous origin of the left coronary artery from the pulmonary artery in adulthood.

A 47-year-old female patient underwent surgical correction of a recently diagnosed anomalous left coronary artery. The artery originated from the pulmonary artery, and the patient had suffered from pulmonary hypertension and congestive heart failure. The follow-up after 3 and 6 months showed only slight improvement in the patient's condition.

[Angioneurotic edema in relation to therapeutic use of angiotensin-converting enzyme inhibitor]. / Angioneurotisk ødem i forbindelse med behandling med angiotensinkonverterende enzym-haemmer.

Angioneurotic oedema secondary to angiotensin-converting enzyme (ACE) inhibitors is a rare condition, but it is a side effect which is likely to be seen more frequently because of the increased use of these drugs in the treatment of heart failure and hypertension. We report two cases which illustrate problems in the diagnosis and management of this life-threatening condition, and also demonstrate that angioedema re-occurs if the ACE inhibitor is not discontinued. If angioedema is suspected, therapy with any angiotensin converting-enzyme inhibitor should be discontinued promptly, respiratory distress should be treated appropriately, and subsequent therapy should be initiated with an agent from an alternative class of drugs.

[Neurohormonal activity in heart insufficiency]. / Neurohormonal aktivitet ved hjerteinsufficiens.

The maintenance of cardiac pumping ability in the presence of a primary disturbance of myocardial contractility and/or an excessive haemodynamic strain on the heart is dependent on several compensatory mechanisms. Particular attention has formerly been paid to the importance of the Frank-Starling mechanism and cardiac hypertrophy and dilatation in maintaining a blood supply sufficient to cover the metabolic needs of various tissues in heart failure. In recent years, however, it has been found that certain neurohormonal systems (the sympathetic nervous system, the renin-angiotensin-aldosterone system, atrial natriuretic peptide and several locally acting vaso-active substances) undergo considerable changes according to the degree of heart failure. These compensatory mechanisms support the circulation wholly or partially in acute heart failure, however sustained neurohormonal activation may be harmful in chronic heart failure, where several neurohormonal factors may be activated to ill-effect. The most significant neurohormonal systems and their importance in heart failure are reviewed on the basis of the available literature.

Neurohormonal systems during progression of heart failure: a review.

In the presence of a primary disorder in myocardial contractility and/or extraordinary hemodynamic pressure on the heart, ventricular performance depends on several compensating mechanisms. In the past, studies were mostly focused on the importance of the Frank-Starling mechanism and the hypertrophy and dilation of the heart in maintaining a circulation sufficient for metabolic intake during heart failure. Recently, however, the existence of neurohormonal systems has been demonstrated (the sympathetic nervous system, the renin-angiotensin system, atrial natriuretic peptide and several locally produced vasoactive substances), which change considerably according to the severity of the heart failure. While these compensatory mechanisms support the circulation in patients with acute heart failure, in whole or in part, neurohormonal activation over an extended period of time might be harmful to patients with chronic congestive heart failure since several neurohormonal factors might be inappropriately activated. This article will review the key neurohormonal systems and their importance in heart failure on the basis of the current literature.

[Young men's contraceptive habits]. / Sessionsindkaldtes praeventionsvaner.

PIP: A total of 379 men from the greater Copenhagen area were invited to fill out a questionnaire about sexual habits and use of contraception in connection with conscription for military duty. A total of 334 (88%) answered the questionnaire. In the autumn of 1988, a total of 27 men answered the test questionnaire, while in the spring of 1989, when the real study was conducted, 307 men answered it. The median age of 334 participants was 18 years (range of 17-29 years). 33% of the group stated that they had used condoms during first intercourse, while 47% had not. 1 person reported to be exclusively attracted sexually to men, 5 persons were attracted both to men and women, but 97% were exclusively attracted to women. 82% had had intercourse or other sexual experience with women. 1.8% had had intercourse or other sexual experience with men. 8% had no sexual experience, and 8% did not answer the question. Oral contraceptives were used by 60% and the condom by 56%. 10% had used coitus interruptus at one time or another; 15% had used no contraception; 5% used the IUD; and 5% used the diaphragm. Some gave several answers. 1% used spermicidal lotion. 60% thought that it was the responsibility of both men and women to be concerned about contraception, 12% opined that it was exclusively men's duty, and 2% that it was exclusively women's, while 26% did not answer. 68% wanted to use the condom in the future for protection, 24% did not know, but 8% did not want to use it more extensively. 64% did not think that the fear of AIDS would affect their sexual life, but 36% thought it would. Several of the subjects indicated that they would be more careful about choosing a partner, and every 10th suggested that they would use the condom with a new partner. One person (0.3%) was a drug addict, 89% had never injected drugs, but about 11% did not answer about drugs. 97% and 95%, respectively, indicated that the condom provided good protection against pregnancy and venereal diseases.^ieng