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Background: Sodium oxybate (SMO) has been shown to be effective in the maintenance of abstinence (MoA) in alcohol-dependent patients in a series of small randomized controlled trials (RCTs). These results needed to be confirmed by a large trial investigating the treatment effect and its sustainability after medication discontinuation. Aims: To confirm the SMO effect on (sustained) MoA in detoxified alcohol-dependent patients. Methods: Large double-blind, randomized, placebo-controlled trial in detoxified adult alcohol-dependent outpatients (80% men) from 11 sites in four European countries. Patients were randomized to 6 months SMO (3.3–3.9 g/day) or placebo followed by a 6-month medication-free period. Primary outcome was the cumulative abstinence duration (CAD) during the 6-month treatment period defined as the number of days with no alcohol use. Secondary outcomes included CAD during the 12-month study period. Results: Of the 314 alcohol-dependent patients randomized, 154 received SMO and 160 received placebo. Based on the pre-specified fixed-effect two-way analysis of variance including the treatment-by-site interaction, SMO showed efficacy in CAD during the 6-month treatment period: mean difference +43.1 days, 95% confidence interval (17.6–68.5; p = 0.001). Since significant heterogeneity of effect across sites and unequal sample sizes among sites ( n = 3–66) were identified, a site-level random meta-analysis was performed with results supporting the pre-specified analysis: mean difference +32.4 days, p = 0.014. The SMO effect was sustained during the medication-free follow-up period. SMO was well-tolerated. Conclusions: Results of this large RCT in alcohol-dependent patients demonstrated a significant and clinically relevant sustained effect of SMO on CAD. Trial registration: ClinicalTrials.gov Identifier: NCT04648423

AimsThe estimated effect of sodium oxybate (SMO) in the treatment of alcohol dependence is heterogeneous. Population severity and treatment duration have been identified as potential effect modifiers. Population severity distinguishes heavy drinking patients with MethodsNetwork meta-regression allows for testing potential effect modifiers. It was selected to investigate the effect of the above factors on SMO efficacy defined as continuous abstinence (abstinence rate) and the percentage of days abstinent (PDA). Randomized controlled trials for alcohol dependence with at least one SMO group conducted in high-severity and mild-severity populations were assigned to a high-severity and mild-severity group of studies, respectively.ResultsEight studies (1082 patients) were retained: four in the high-severity group and four in the mild-severity group. The high-severity group was associated with larger SMO effect sizes than the mild-severity group: abstinence rate risk ratio (RR) 3.16, P = 0.004; PDA +26.9%, P ConclusionsIn the retained studies with alcohol-dependent patients, high-severity population and longer treatment duration were associated with larger SMO effect sizes.

International audience; Background: There is considerable unexplained variability in alcohol abstinence rates (AR) in the placebo groups of randomized controlled trials (RCTs) for alcohol dependence (AD). This is of particular interest because placebo responses correlate negatively with treatment effect size. Recent evidence suggests that the placebo response is lower in very heavy drinkers who show no "spontaneous improvement" prior to treatment initiation (high-severity population) than in a mild-severity population and in studies with longer treatment duration. We systematically investigated the relationship between population severity, treatment duration, and the placebo response in AR to inform a strategy aimed at reducing the placebo response and thereby increasing assay sensitivity in RCTs for AD.Methods: We conducted a systematic literature review on placebo-controlled RCTs for AD.We assigned retained RCTs to high- or mild-severity groups of studies based on baseline drinking risk levels and abstinence duration before treatment initiation. We tested the effects of population severity and treatment duration on the placebo response in AR using meta-regression analysis.Results: Among the 19 retained RCTs (comprising 1996 placebo-treated patients), 11 trials were high-severity and 8 were mild-severity RCTs. The between-study variability in AR was lower in the high-severity than in the mild-severity studies (interquartile range: 7.4% vs. 20.9%). The AR in placebo groups was dependent on population severity (p = 0.004) and treatment duration (p = 0.017) and was lower in the high-severity studies (16.8% at 3 months) than the mild-severity studies (36.7% at 3 months).Conclusions: Pharmacological RCTs for AD should select high-severity patients to decrease the magnitude and variability in the placebo effect and and improve the efficiency of drug development efforts for AD.

Die Antwort der Gesellschaft auf die alte Frage – was einen Suchtkranken dazu verleitet Alkohol, Tabak oder Drogen (erneu) zu konsumieren – auch nachdem ihr Leben bereits signifikant von diesen geschadigt wurde – fuhrt oft zu einer allzu simplen Antwort: Schwacher Wille!

Suchtmittel sind primar meist pflanzlicher Natur, und sie sind sicher alter als die Menschheit. Es sind pharmakologisch wirksame Substanzen, und sie folgen damit naturlich auch den anerkannten pharmakologischen Regeln. Tausende von Jahren wurden sie von der Menschheit verwendet, und man behandelte mit Suchtmitteln die verschiedensten Erkrankungen. Schon seit mehr als 2000 Jahren weis man, dass man mittels Rauch (Feuer- oder Tabakrauch) und auch mit Alkohol Krankheitserreger vertreiben kann. Noch vor 150 Jahren fuhrte auch in Europa kontaminiertes Wasser haufig zu schweren korperlichen Beschwerden (auch mit Todesfolge). Diese gesundheitsschadigenden Wirkungen konnten beim Alkoholkonsum von Getranken, die nur einen niederen Alkoholgehalt hatten, in keiner Weise beobachtet werden. Alkohol wird nach wie vor als Desinfektionsmittel verwendet, und Schamanen am oberen Amazonas verwenden den Rauch von Tabak auch heute noch, um Krankheitserreger wegzublasen. Die psychopharmakologischen Auswirkungen von Alkohol waren immer schon bekannt, und es gab in praktisch allen Kulturen klare Regeln, in welcher Dosierung und zu welchen Zeitpunkten oder Gelegenheiten Alkohol und Tabak konsumiert werden durften, ja sogar genossen werden sollten (Rituale bei den Indianern [z. B. Friedenspfeife] oder vorgeschriebene Trinkgelage in der mexikanischen Kultur). Wenn man sich an dieseRituale nicht gehalten hat, waren Alkohol- und Tabakkonsum allerdings auch immer mit schwersten Strafen bis zur Todesstrafe verbunden.

Da Alkohol- und Tabakkonsum haufig miteinander vorkommen, hat sich das wissenschaftliche Interesse an beiden Suchtmitteln in den letzten Jahren deutlich erhoht. Das Schadigungspotenzial beim gemeinsamen Gebrauch ist wesentlich hoher als das von Alkohol oder Tabak allein. In der Praxis schildern Patienten haufig, dass sie eine der Abhangigkeiten problemlos beenden konnten, aber seit dieser Zeit sich das Einnahmeverhalten gegenuber anderen Substanz deutlich verschlechtert hatte (z. B. gelingt es Patienten, problemlos mit dem Rauchen aufzuhoren, aber anschliesend wurde der Alkoholmissbrauch deutlich problematischer). Nachdem wir immer mehr uber die Entwicklung von Abhangigkeitserkrankungen wissen, und die Basisforschung immer besser erklaren kann, wie die einzelnen Regelkreise des Gehirns funktionieren, ist es uns ein Anliegen, auch den klinisch Tatigen die Unterlagen zu liefern, die sie in der Therapie oder auch Beratung von Tabak- und Alkoholabhangigen benotigen. Die Differenzierung zwischen Phanomenen wie Belohnungssystem, Suchtgedachtnis, Entzugserscheinungen oder auch dem Verlangen (Craving) nach Tabak und Alkohol ist heute unbedingt notwendig, um eine rationale Therapie und Beratung durchzufuhren. In der Literatur (Bleuler 1983; Forel 1930, 1935; Haller 2007; Konsensus-Statement: Substanzbezogene Storungen und psychiatrische Erkrankungen 2007) werden noch immer sehr alte Konzepte vertreten, die dann in allgemeine Regeln zur Therapie von Abhangigen munden, wobei man haufig bemerkt, dass von den Autoren Wertvorstellungen vertreten werden, die heute nicht mehr akzeptiert werden konnen. Ruckfall wird immer als etwas Negatives gesehen, und auch das negative Stigma der Diagnose Abhangigkeit stellt noch immer ein groses Problem dar. Dieses Buch will versuchen, sachliche Informationen zu liefern, die bewusst machen, dass der Verlauf von Abhangigkeitserkrankungen nichts mit Schuld oder personlicher Schwache zu tun hat. Die praktisch Tatigen haben sich von diesen allgemeinen Therapierichtlinien meist gelost und vertreten ein Konzept der „individuellen Therapie“ fur jeden Patienten. Diese Therapien heisen dann Therapie nach Dimensionen oder ressourcenorientierte Therapie oder auch Therapie, die nicht veranderbare Variable akzeptiert und veranderbare Variable zu beeinflussen versucht. Prinzipiell ist diesen modernen Ansatzen aus meiner Sicht zuzustimmen, in diesem Buch werden Faktoren dargestellt werden, die allgemeine Gultigkeit haben und in der Therapie von Abhangigkeitserkrankungen bei den meisten Patienten hilfreich sind. Die wissenschaftlichen Ergebnisse zu Untergruppen nach der Typologie nach Lesch stellen Grundlagen fur die Therapie dar, die individuell oft noch modifiziert werden mussen. Der Veranderungswunsch sollte verstarkt werden und die Verbesserung der Veranderungskompetenz stellt den Anfang jeder Therapie dar. Gerade zur Motivationsarbeit nach den Untergruppen und zur Anticraving Medikation gibt es neue Daten, die eine 2. Auflage notwendig machten. Henriette Walter und ich haben in der 2. Auflage noch andere Experten um Hilfe gebeten, die sich vor allem aus psychologischer und neurophysiologischer Sicht mit dem Thema Motivation beschaftigen.

60 % der Tabakabhangigen beschreiben sich als dissonante Raucher. Sie versuchen dauernd oder zeitweilig, das Rauchverhalten zu reduzieren oder auch aufzuhoren. Sie wissen sehr genau, dass ihr Rauchen zu Folgekrankheiten fuhrt. Sie kennen meist ihre Entzugssymptome, aber die echte Motivation, Hilfe von ausen zu suchen, benotigt in dieser Gruppe oft noch einen Anstos durch die soziale Situation (Partner, Arbeitssituation usw.) oder durch korperliche Symptome (Atemnot bei Belastung, Magenschmerzen, Schwangerschaft usw.). Wenn diese Gruppe einen Therapeuten aufsucht, wissen diese dissonanten Raucher, dass sie ein gewisses Abhangigkeitsproblem haben. Bei einer wirksamen Hilfe sind sie meist leicht zu motivieren, das Rauchverhalten zu reduzieren oder sogar einzustellen (Kunze et al. 2009; Balfour et al. 2000).

Bei allen Erkrankungen werden psychologische, soziale, biologische und genetische Ursachen vermutet. Nur wenige dieser atiologischen Uberlegungen fuhren jedoch zu praktisch therapeutisch verwertbaren Ansatzen. Auch bei den Abhangigkeitserkrankungen wird immer wieder postuliert, dass psycho-bio-soziologische atiologische Faktoren zu definieren sind. Die Heterogenitat der Abhangigkeitserkrankungen, die heute unbestritten ist, wird in den Kap. 5 und 6 abgehandelt, und naturlich haben die Untergruppen von Abhangigkeitserkrankungen auch alle psycho-bio-soziologische atiologische Faktoren, aber die Gewichtung und die Bedeutung der einzelnen Faktoren sind je nach Untergruppe sehr unterschiedlich. Alkohol- und Tabakabhangige, die regelmasig mit Alkohol und Tabak ihre Entzugssymptome bekampfen, sonst aber von der Personlichkeit her und seitens des sozialen Umfelds keinerlei Auffalligkeiten zeigen, unterscheiden sich atiologisch ganz klar von Alkohol- und Tabakabhangigen, die Alkohol und Tabak zur Stressbekampfung in bestimmten Situationen benutzen und keine oder nur milde Entzugserscheinungen haben.

85 % aller Erwachsenen in Mitteleuropa trinken mehr oder weniger regelmasig Alkohol, und deshalb wird die Frage „Trinken Sie Alkohol?“ fast immer positiv beantwortet. Diese Antwort gibt aber keine Information zur Interaktion der psycho-sozio-biologischen Beschwerden mit der Wirkung des Alkohols, und deshalb sollte diese Frage vermieden werden. Missbrauchende und Abhangige kennen ihr Problem, erleben ihr Problem haufig als eigenes Versagen und haben haufig Schuld- und Schamgefuhle. Hervorragend hat diese Situation Antoine de Saint-Exupery im 12. Kapitel seines Buches „Der kleine Prinz“ (1943) beschrieben (Abb. 8.1)

Wie bereits im letzten Kapitel betont, ist seit langem bekannt, dass Alkoholabhangige keine homogene Population darstellen. Studien, die zur Gruppenbildung das DSM-IV verwendet haben, konnten zeigen, dass der groste Teil der Patienten entweder eine zweite Achse-I-Diagnose oder eine Achse-II- oder sowohl eine Achse-I- als auch eine Achse-II-Diagnose hat.

Die Diagnosesysteme in der Psychiatrie versuchen, homogene Gruppen zu definieren, die zu Hypothesen fuhren, welche spezifische Atiologie bestimmte Syndrome bewirkt, und aus der Atiologie sollte abgeleitet werden konnen, welche spezifische Therapie fur diese Krankheitsgruppe zu den besten Ergebnissen fuhrt. Fur die Diagnose einer Erkrankung waren folgende Voraussetzungen wunschenswert

Introduction: Sodium oxybate (SMO) has been approved in Italy and in Austria for the treatment of alcohol use disorder (AUD). This study describes the cumulative postmarketing and clinical safety experience with SMO in AUD. Areas covered: Safety data for SMO at approved posology in AUD were identified from: (i) the clinical trial registries of the US National Institutes of Health (NIH) and the European Medicines Agency (EMA), (ii) reports from the biomedical literature and (iii) available pharmacovigilance safety information from the EMA. Expert opinion: Safety data from 3 recent large randomized clinical studies (520 participants) and 43 earlier clinical studies (2547 participants) showed that SMO has a good safety profile in AUD patients. The safety profile was confirmed by pharmacovigilance data resulting from 299 013 patients exposed to SMO in Austria and Italy. Main adverse events were transitory dizziness and vertigo. Serious adverse events were rare. No death attributable to SMO has been reported. Risks of abuse or dependence are low in patients without psychiatric comorbidities or poly-drug use. The adverse events of SMO are transitory and do not require discontinuation of treatment. SMO abuse or dependence are extremely rare in patients without psychiatric comorbidities or poly-drug use.

This study intended to determine whether certain traits of temperament are associated with former and current ADHD symptomatology in a non-clinical sample of 18 year old males.We performed a cross sectional descriptive study of 3280 men during the examination for military service. The investigation included a socio-demographic questionnaire, screening for substance abuse, temperament (TEMPS-M), past (WURS) and current (ADHD symptom checklist) ADHD symptomatology.We found a correlation of cyclothymic (p.001), irritable (p.001) and anxious (p.05) temperament with occurrence and severity of past and present ADHD symptomatology. No significant correlation has been detected for hyperthymic and depressive temperament. Judged retrospectively, ADHD symptoms were strongly consistent over time.The sample consists of men only. These had to be fit enough to be enlisted for military service; men with severe mental or physical disorders were thus excluded. Furthermore, the cross-sectional study design does not allow making conclusions about the temporal relationships between ADHD symptoms and substance misuse.These results indicate that a temperament based approach towards those affected by ADHD might be useful. Subtyping ADHD by integrating temperament profiles in diagnosis and treatment of the disorder could help explain some of the heterogeneity of the disease.

Background Substance abuse is among the leading causes of preventable diseases and premature death but reasons and conditions leading to substance abuse are complex and multifaceted. Different models of abuse and dependence assume an underlying emotional vulnerability. Individual behavioral and emotional reactivity patterns of personality are considered in the concept of temperament but studies linking different types of temperament with substance use are rare. Methods In this study we investigated 1380 inhabitants (59.7% females; 40.3% males) of residential student homes in Austria, using Akiskals TEMPS-M auto-questionnaire. Further, we administered the CAGE- and the HSI-questionnaire and assessed other psychoactive substance use to examine associations between traits of temperament and substance abuse using ordered logistic regression. Results Temperaments follow different distributions in both genders: Women have higher scores on the depressive, cyclothymic, and anxious subscales and lower scores on the hyperthymic scale than men. The cyclothymic and particularly irritable temperament serve as predictors of self-reported nicotine dependence, alcohol abuse and cannabis use. Interestingly, the depressive temperament seems to be protective against self-reported cannabis use. Limitations Substance abuse assessment is based on self-reports only and urine drug and blood tests were not performed. Also, the history of substance abuse is not documented thus temperamental factors could have been influenced by substance abuse if the time of onset was in early adolescence. The study design was cross-sectional, thus limiting causal interpretations. Conclusions It might be important to consider temperamental traits as protective- and risk factors in the etiology, prevention and therapy of substance abuse in future.

Multiple lines of evidence suggest that the endocannabinoid system is implicated in the development of alcohol dependence. In addition, in animal models, the cannabinoid receptor 1 blocker rimonabant was found to decrease alcohol consumption, possibly by indirect modulation of dopaminergic neurotransmission. This was a 12-week double-blind, placebo-controlled, proof-of-concept study to assess the possible efficacy of the cannabinoid receptor 1 antagonist rimonabant 20 mg/d (2 x 10 mg) in the prevention of relapse to alcohol in recently detoxified alcohol-dependent patients. A total of 260 patients were included, 258 were exposed to medication, and 208 (80.6%) were men. Patients had an alcohol history of 15 years on average. More patients in the rimonabant group (94/131 [71.8%]) completed treatment compared with the placebo group (79/127 [62.2%]). Although there was a modest effect of rimonabant with respect to relapse rate, there were no statistically significant differences between treatment groups. Approximately 41.5% of the rimonabant group had relapsed to drinking at the end of the study compared with 47.7% of the placebo group (obtained from Kaplan-Meier-curve). Differences were more marked but not statistically significant in patients who relapsed to heavy drinking: 27.7% versus 35.6%, respectively. Safety and tolerance of the drug were good. Similar rates of adverse events were reported between the 2 groups; less patients experienced serious events or discontinued the treatment with rimonabant compared with placebo. Rates of depression-related events were low (3.8% with rimonabant compared with 1.6% with placebo). Patients on rimonabant lost weight (Mean, -1.7 kg) compared with baseline, whereas there was no such change in the placebo group. Weight loss was more pronounced in patients with a higher body mass index. In addition, there was a significant decrease in leptin levels in the rimonabant group compared with baseline. Lack of efficacy in this study may be explained by a very high response rate in the placebo group and a relatively short treatment duration. Taking the substantial numbers of animal studies suggesting a possible role of CB1 antagonists for the treatment of alcohol dependence into account, it seems worthwhile to further test cannabinoid blockers in the treatment of alcoholism.

Objective. To validate NAT (NETER's alcoholic typology), taking into account the differentiated distribution of the measures used as external criteria in alcohol-dependent sub-groups and its relationship with Lesch's alcoholic typology (LAT). Method. A sample of 133 alcohol-dependent patients integrated in the alcoholism unit of the Psychiatric Service of Santa Maria University Hospital were included in the study. Results and Conclusions. Convergent validity was assured by the agreement between the subtypes of the two typologies (NAT and Lesch), considering the same underlying model of alcoholism development: anxiopathic subtype of NAT and Type II (model of anxiety, alcohol as conflict solution) of Lesch and the tymopathic subtype of NAT and type III (model of depression, alcohol as antidepressant) of Lesch. Discriminant analysis (external criteria) showed significant differences between the subtypes in the following variables: gender; tobacco; beer and whisky consumption; daily average of drinks; clinical conditions such as delirium tremens, alcoholic blackouts and seizures; severity of alcohol-related problems; psychological dimensions such as psychological maturity and extroversion; and suicidal ideation during the alcohol consumption period. A more exhaustive description of alcoholic sub-groups may improve genetic studies of alcoholism and provide the alcoholic patient with an adequate specific therapeutic protocol.

¶Alcohol abuse and alcoholism cut across gender, race and nationality. In general, more men than women are alcohol dependent or have alcohol problems, but women are at greater risk for adverse effects and alcohol-related diseases. Death rates among female alcoholics are 50 to 100 percent higher than those of men. Major physiological impairments, the diagnostic distribution, the psychosocial consequences and their implication on treatment will be outlined.

Aims The first aim of this study is to investigate the impact of different temperaments in opiate dependency patients. The second aim of this study is to define therapy relevant subgroups in opiate addiction for further basic clinical research and therapy. Methods In the time period from September to November 2010, 101 patients (72 males and 29 females) which fulfilled the diagnosis of opiate dependency according to DSM-IV-TR were recruited consecutively. All patients were in treatment at the Oum El Nour rehabilitation center/Lebanon (Inpatient and Outpatient groups). Lesch Alcoholism Typology modified for assessment of opiate addicts, and the briefTEMPS-M, Arabic version were used. Results The organic Type IV group was the most prevalent (48.5%) among the sample followed by the Affective Type III group (41.6%) and the minority represented the two other types (I & II). The organic Type IV group represented the major type in the cyclothymic and anxious temperament. In the contrary the other two groups (I & II) were the minority among the cyclothymics.

Over the past several years, the editors of leading international cardiovascular journals have met to form the HEART Group and to discuss areas of growing, common interest. Recently, the HEART Group has developed a document that addresses general ethical principles in the conduct of the scientific process with which all of the editors concur. Published essentially simultaneously in all of the participating journals, including this journal, this document presents the ethical tenets accepted by all of the undersigned editors that will (continue to) guide their decisions in the editorial process. These are the general principles on which the HEART Group is based and by which we, as a group, abide; however, please note that individual journal members and their respective societies may have their own rules and regulations that supersede the guidelines of the HEART Group. Acta Cardiologica Hugo Ector, MD, PhD Editor-in-Chief Patrizio Lancellotti, MD Editor-in-Chief American Journal of Cardiology William C. Roberts, MD Editor-in-Chief American Journal of Geriatric Cardiology Nanette K. Wenger, MD Editor-in-Chief Annals of Noninvasive Electrocardiology Arthur J. Moss, MD Editor-in-Chief Canadian Journal of Cardiology Eldon R. Smith, MD Editor-in-Chief Cardiology Jeffrey S. Borer, MD Editor-in-Chief Cardiosource Review Journal Kim A. Eagle, MD Editor-in-Chief Cardiovascular Drug Reviews Jane Freedman, MD Incoming Editor-in-Chief Henry Krum, PhD Incoming Editor-in-Chief Chim Lang, MD Incoming Editor-in-Chief Cardiovascular Drugs and Therapy Willem J. Remme, MD, PhD Editor-in-Chief Cardiovascular Research Hans Michael Piper, MD, PhD Editor-in-Chief Catheterization and Cardiovascular Interventions Christopher J. White, MD Editor-in-Chief Circulation Joseph Loscalzo, MD, PhD Editor-in-Chief Circulation Research Eduardo Marban, MD, PhD Editor-in-Chief Coronary Artery Disease Burton E. Sobel, MD Editor Current Opinion in Cardiology Robert Roberts, MD Editor Current Problems in Cardiology Shahbudin H. Rahimtoola, MD Editor Europace A. John Camm, MD Editor-in-Chief European Heart Journal Frans Van de Werf, MD Editor-in-Chief European Journal of Heart Failure Karl Swedberg, MD, PhD Editor-in-Chief Heart Adam D. Timmis, MD Editor Heart & Lung: The Journal of Acute and Critical Care Kathleen S. Stone, PhD, RN Editor-in-Chief Heart Rhythm Douglas P. Zipes, MD Editor-in-Chief International Journal of Interventional Cardioangiology David G. Iosseliani, MD Editor-in-Chief Journal of Cardiovascular Computed Tomography Allen J. Taylor, MD Editor-in-Chief Journal of Cardiovascular Pharmacology Michael R. Rosen, MD Editor Journal of Interventional Cardiology Cindy L. Grines, MD Editor-in-Chief Journal of the American College of Cardiology Anthony N. DeMaria, MD Editor-in-Chief JACC: Cardiovascular Imaging Jagat Narula, MD, PhD Editor-in-Chief JACC: Cardiovascular Interventions Spencer B. King III, MD Editor-in-Chief Journal of Electrocardiology Galen S. Wagner, MD Editor-in-Chief Journal of Interventional Cardiac Electrophysiology Sanjeev Saksena, MD Editor-in-Chief Journal of the American Society of Echocardiography Alan S. Pearlman, MD Editor-in-Chief Journal of Heart Valve Disease Endre Bodnar, MD, PhD Editor-in-Chief Robert W. Emery, MD Incoming Editor-in-Chief Journal of Thoracic and Cardiovascular Surgery Lawrence H. Cohn, MD Editor-in-Chief Netherlands Heart Journal Ernst E. van der Wall, MD Editor-in-Chief Pediatric Cardiology Ra-id Abdulla, MD Editor-in-Chief Progress in Cardiovascular Diseases Michael Lesch, MD Editor Revista Espanola de Cadiologia Fernando Alfonso, MD, PhD Editor-in-Chief Scandinavian Cardiovascular Journal Rolf Ekroth, MD Chief Editor

Background —Alterations in K + channel expression and gating are thought to be the major cause of action potential remodeling in heart failure (HF). We previously reported the existence of a late Na + current (I NaL ) in cardiomyocytes of dogs with chronic HF, which suggested the importance of the Na + channel in this remodeling process. The present study examined whether this I NaL exists in cardiomyocytes isolated from normal and failing human hearts. Methods and Results —A whole-cell patch-clamp technique was used to measure ion currents in cardiomyocytes isolated from the left ventricle of explanted hearts from 10 patients with end-stage HF and from 3 normal hearts. We found I NaL was activated at a membrane potential of −60 mV with maximum density (0.34±0.05 pA/pF) at −30 mV in cardiomyocytes of both normal and failing hearts. The steady-state availability was sigmoidal, with an averaged midpoint potential of −94±2 mV and a slope factor of 6.9±0.1 mV. The current was reversibly blocked by the Na + channel blockers tetrodotoxin (IC 50 =1.5 μmol/L) and saxitoxin (IC 50 =98 nmol/L) in a dose-dependent manner. Both inactivation and reactivation of I NaL had an ultraslow time course (τ≈0.6 seconds) and were independent of voltage. The amplitude of I NaL was independent of the peak transient Na + current. Conclusions —Cardiomyocytes isolated from normal and explanted failing human hearts express I NaL characterized by an ultraslow voltage-independent inactivation and reactivation.

Cardiomyocyte apoptosis or programmed cell death has been shown to occur in end-stage explanted failed human hearts and in dogs with chronic heart failure (HF). We tested the hypothesis that early long-term monotherapy with an angiotensin-converting enzyme (ACE) inhibitor attenuates cardiomyocyte apoptosis in dogs with moderate HF. Left ventricular (LV) dysfunction (ejection fraction 30–40%) was produced in dogs by multiple sequential intracoronary microembolizations. Dogs were randomized to 3 mo of therapy with enalapril (Ena, 10 mg twice daily, n = 7) or to no therapy at all (control, n = 7). After 3 mo of therapy, dogs were euthanized and the hearts removed. Presence of nuclear DNA fragmentation (nDNAf), a marker of apoptosis, was assessed in frozen LV sections using the immunohistochemical deoxynucleotidal transferase-mediated dUTP-digoxigenin nick-end labeling (TUNEL) method. Sections were also stained with ventricular anti-myosin antibody to identify cells of cardiocyte origin. From each dog, 80 fields (×40) were selected at random, 40 from LV regions bordering old infarcts and 40 from LV regions remote from any infarcts, for quantifying the number of cardiomyocyte nDNAf events per 1,000 cardiomyocytes. The average number of cardiomyocyte nDNAf events per 1,000 cardiomyocytes was significantly lower in Ena-treated dogs compared with controls (0.81 ± 0.13 vs. 2.65 ± 0.81, P < 0.029). This difference was due to a significantly lower incidence of cardiomyocyte nDNAf events in LV regions bordering scarred tissue (infarcts) in Ena-treated dogs compared with controls. We conclude that early long-term Ena therapy attenuates cardiomyocyte apoptosis in dogs with moderate HF. Attenuation of cardiomyocyte apoptosis may be one mechanism by which ACE inhibitors preserve global LV function in HF.

BACKGROUND Heart failure therapy with beta-receptor blockade has been shown to effect a partial reversal of left ventricular (LV) remodeling in heart failure. HYPOTHESIS We tested the hypothesis that, in the absence of beta blockade, uptitration of angiotensin-converting enzyme (ACE) inhibitor and nitrate therapy over conventional dosages would improve symptoms as well as LV function in patients with severe heart failure. METHODS For patients with nonischemic or ischemic cardiomyopathy, intensive high-dose angiotensin-converting enzyme inhibitor and nitrate therapy was uptitrated. Echocardiograms were obtained semiannually and evaluated in a blinded fashion. Of 99 patients in the study, aged 55 +/- 13 years, with heart failure for 5.2 +/- 3.1 years, 74 were men, 69 were Caucasian, and 34 had ischemic cardiomyopathy. The final dosage of enalapril was 40 +/- 23 mg/day of isosorbide dinitrate it was 153 +/- 127 mg/day. RESULTS Initial New York Heart Association classification improved from 2.8 +/- 0.9 to 1.7 +/- 0.9 (p < 0.001) in 2.7 years of follow-up. Of the 99 patients, 72 further improved their ejection fraction. For the whole group, ejection fraction increased from 21 +/- 9% to 30 +/- 13% in 6 months (p < 0.001), with a reduction in LV end-diastolic size from 6.6 +/- 0.9 to 6.3 +/- 1.0 cm (p = 0.002), a decrease in the severity of mitral regurgitation from mild/moderate to only mild. Resting heart rate declined with no change over time in systemic systolic blood pressure. Final ejection fraction for nonischemic patients (n = 65) was 36 +/- 16% versus 23 +/- 9% for the ischemic population. CONCLUSIONS Uptitration of high-dose ACE inhibitor and nitrate therapy to higher doses is well tolerated in severe heart failure, further improves both clinical status and LV systolic function, and is more effective in nonischemic than in ischemic cardiomyopathy.

Progressive deterioration of left ventricular function is a characteristic feature of the heart failure state and is often speculated to result from ongoing loss of viable myocytes. We previously showed that in dogs with chronic heart failure, cardiocyte death through apoptosis occurs in the border region of fibrous scars (old infarcts). In the present study we examined the structural integrity of cardiocytes in regions bordering fibrous scars using transmission electron microscopy. Morphometric studies were performed using left ventricular tissue obtained from ten dogs with chronic heart failure produced by intracoronary microembolizations. Mitochondrial number increased significantly with proximity to the scar, while mitochondrial size decreased leading to a gradual decrease in mitochondrial volume fraction. Severe injury to mitochondria was present in only 5% of organelles in myocytes far from the scar but increased markedly to 28-41% in myocytes adjacent to or incorporated within the scar. Similarly, severe myofibrillar abnormalities were present in only 3% of myocytes that were far from the scar but increased significantly to 12-73% in myocytes adjacent to or incorporated within the scar. These results indicate that in dogs with chronic heart failure, constituent myocytes of left ventricular regions bordering fibrous scars manifest heterogeneity in the extent of degeneration. The extent of degeneration is greatest in myocytes closest to the scar and least in myocytes far from the scar. We postulate that this wavefront of myocyte degeneration is a dynamic process that may lead to progressive expansion of the scar through loss of viable myocytes and ultimately may contribute, in part, to the progressive left ventricular dysfunction that characterizes the heart failure state.

Protein phosphatase inhibitor-1 (PPI-1) has been shown to be present in heart tissue and smooth muscle. Whether PPI-1 is present in cardiomyocytes is not known. The purpose of this study was to determine whether PPI-1 is present and is hormonally regulated in cardiomyocytes. A trichloroacetic acid (TCA) extract enriched in PPI-1 was isolated from guinea pig ventricular cardiomyocytes. The TCA extract inhibited the activity of type 1 protein phosphatase by 20 +/- 4% (n = 3 expts). On phosphorylation by the catalytic subunit of adenosine 3', 5'-cyclic monophosphate-dependent protein kinase, the extent of this inhibition was augmented to 4.5-fold. Dephosphorylation of the phosphorylated TCA extract by type 2 protein phosphatase reduced inhibition to 2 +/- 0.2% (n = 3 expts). To determine whether isoproterenol increases phosphorylation of PPI-1 in cardiomyocytes, the TCA extracts were prepared from cardiomyocytes treated with 1 microM isoproterenol and from untreated cardiomyocytes. The inhibitory activity of the TCA extract in untreated cardiomyocytes was 25 +/- 3% (n = 3 expts) and increased to 75 +/- 2% (n = 3 expts) in isoproterenol-treated cardiomyocytes. With the use of a rabbit skeletal muscle PPI-1 antibody, immunoblots of the TCA extract of cardiomyocytes identified a 28-kDa protein. A 28-kDa protein was also immunoprecipitated from a TCA extract isolated from isoproterenol-treated 32P-labeled cardiomyocytes. The immunoprecipitation was blocked by the addition of excess amounts of purified rabbit skeletal muscle PPI-1. Isoproterenol-treated cardiomyocytes increased the phosphorylation of the 28-kDa protein by 232 +/- 20% (n = 3 expts) compared with untreated cardiomyocytes. We conclude that 1) the 28-kDa protein is PPI-1, 2) PPI-1 is present in ventricular cardiomyocytes, and 3) PPI-1 is hormonally regulated. A decrease in type 1 protein phosphatase activity through phosphorylation of PPI-1 may be an important pathway for augmenting cardiac contractility.

Internal medicine training programs must adapt to health care systems faced with balancing the competitive priorities of patient-care responsibilities and educational needs.To evaluated the effects of a major organizational change on the inpatient service of an internal medicine residency program in a vertically integrated health system.We changed the structure of our program from a system in which the hospitalized patients' primary physicians were responsible for daily inpatient management, while teaching was assigned to a defined teaching rounder, to a method in which the rounding attending was responsible for both teaching and patient care. Measurements before and after the change in the rounding system included: the McGill University clinical tutor evaluations, time-motion observations of house staff, patient satisfaction surveys, average length of stay data, and physician focus groups to assess physician satisfaction.The rounding attendings consistently received excellent to superior ratings by the house staff both before and after the implemented change. Compared to time-motion observations performed before the change, observations recorded after the change suggested that a greater percent of house staff time was spent on educational activities. The responses of patient satisfaction surveys indicated that the perception of quality of care remained high after the system change. Lastly, the average length of stay for patients on the general internal medicine and subspecialty services was reduced from 7.6 days before the change to 6.6 days after the change, a difference of 0.92 day (95% confidence interval 1.3 to 0.6, P0.001).Through organizational restructuring, it is possible to improve the quality of patient care and improving the efficiency of patient-care management.

We examined the incidence and severity of abnormalities of contractile structures of residual viable cardiomyocytes in the left ventricular free wall, septum and right ventricular free wall of 10 dogs with chronic heart failure produced by multiple intracoronary microembolizations and in septal biopsies of 13 patients with chronic heart failure. The abnormalities were evaluated by transmission electron microscopy and classified as either (i) type-1, defined as complete interruption of myofibrils; (ii) type-2, defined as disconnection of end-sarcomeres from the intercalated disc; or (iii) type-3, sarcomere abnormalities defined as Z-bands irregularities and/or focal myofilament disarray. In the left ventricular free wall of dogs, type-1 abnormalities were present in 33 +/- 8% of myocytes, type-2 in 26 +/- 8%, and type-3 in 63 +/- 9%. The incidence of a type-3 abnormality but not type-1 or type-2 was greater in the left ventricular wall compared with the septum and right ventricular wall (P0.05). Among abnormal myocytes, 29 +/- 3% of myofibrils were interrupted, 18 +/- 4% of end-sarcomeres were disconnected from the intercalated disc and 12 +/- 2% of sarcomeres were abnormal. The severity of a type-1 but not type-2 or type-3 abnormalities was greater in the left ventricular wall compared with the septum and right ventricular wall. A similarly high incidence of abnormalities was observed in septal myocytes of patients. The results indicate that abnormalities of contractile structures are common among viable myocytes of the failing heart. The incidence of these abnormalities is sufficiently high to warrant serious consideration of their potential role in the progression of left ventricular dysfunction that characterizes the heart failure state.

Patients with acute vascular disorders of the CNS demonstrate an abundance of both rhythm and morphologic changes in their ECG. Of these a few will demonstrate myocardial dysfunction and or damage. The value of the ECG in evaluating and predicting which patients will have myocardial dysfunction or damage is questionable. One would assume the echocardiogram would be of more help than the ECG in identifying patients with myocardial damage; however, little data are available. The reason for the poor correlation between ECG findings and clinical correlates has not been explained to date, but it is possible to postulate a theory. There are two mechanisms that might mediate ECG changes in these patients, ie, autonomic neural stimulation from the hypothalamus or elevated circulating catecholamines. Hypothalamic stimulation may cause ECG changes without associated myocardial damage whereas elevated catecholamines may result in myocardial damage. This might explain why so many patients have ECG changes and very few have demonstrable myocardial damage in general, or ischemic damage in particular. That cardiac antiischemic therapy does not change mortality may relate to the fact that treatment has been directed towards patients with ECG changes, which in turn do not correlate with myocardial damage. Better patient selection for such therapy might rest upon demonstration of wall motion abnormalities on echocardiogram. The weakness of this strategy is that many patients with stroke have preexisting coronary disease and wall motion abnormalities and thus echo findings may only document remote infarction rather than acute ischemia.

When rabbit ventricular myocytes were cultured for 1 wk and then exposed to alpha- and/or beta-adrenergic agonists, such nonbeating heart cell preparations disclosed increased protein-to-DNA ratios and elevated RNA content, indicative of cellular hypertrophy. Norepinephrine, isoproterenol, and phenylephrine provoked hypertrophy with norepinephrine eliciting a greater response than isoproterenol or phenylephrine. Specific alpha- and beta-antagonists blocked growth by inhibiting catecholamine-induced changes in protein turnover. Each catecholamine enhanced the fractional rate of protein synthesis within 48 h; however, changes in growth rates appeared to be modulated, in part, by alterations in protein degradation. Even though rates of total protein and actin synthesis resembled values measured in vivo, myosin heavy chain fractional rate of synthesis was only 22% of in vivo levels. Double label immunofluorescence microscopy further illustrated that catecholamine treatment accelerated myofibrillar disruption in these quiescent heart cells. These observations suggested that in the absence of beating, neurohumoral modulation of contractile protein turnover was not associated with the maintenance of myofibrillar integrity even though catecholamines induced cellular hypertrophy.

BACKGROUND Whether biochemical and histological abnormalities of skeletal muscle (SM) develop in patients with chronic heart failure (HF) remains controversial. In the present study, dogs with chronic HF were used to examine potential alterations of SM fiber type, fiber size, number of capillaries per fiber (C/F), beta-adrenergic receptor density (Bmax), and fiber ultrastructural integrity. METHODS AND RESULTS HF was produced in 17 dogs by sequential intracoronary microembolizations. Biopsies of the lateral head of the triceps muscle were used in all studies. Type I and type II fibers were differentiated by myofibrillar ATPase (pH 9.4 or 4.2). Bmax was assessed by radioligand binding and SM ultrastructure by transmission electron microscopy. Comparisons were made with biopsies obtained from nine control dogs. The percentage of SM type I fibers was reduced in HF dogs compared with control dogs (19 +/- 2% versus 32 +/- 5%) (p < 0.001), whereas the percentage of SM type II fibers was increased (81 +/- 2% versus 68 +/- 5%) (p < 0.001). The change in fiber type composition was not associated with a preferential atrophy or hypertrophy of either fiber type. There was no difference in SM Bmax (198.9 +/- 14.3 versus 186.8 +/- 17.3 fmol/mg protein) or in C/F (5.37 +/- 0.26 versus 5.84 +/- 0.21) between HF dogs and control dogs. No ultrastructural abnormalities were present in SM fibers of HF dogs. CONCLUSIONS In dogs with HF, there is a decrease in the relative composition of the slow-twitch type I SM fibers and an increase in fast-twitch type II fibers. The shift in fiber type composition is not associated with preferential atrophy of either fiber type or with a reduction in C/F, beta-adrenergic receptor density, or structural abnormalities of the myofibers.