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Previous studies established a role for the wearable cardioverter defibrillator (WCD) to effectively and safely bridge temporary risk for sudden cardiac death (SCD) in patients with advanced heart failure. The prognostic relevance of the WCD remains controversial.The authors investigated adherence to, as well as the safety and effectiveness of, WCD use in a real-world cohort of patients at high risk for SCD.All consecutive patients (n = 83) receiving a WCD at a German tertiary care hospital between April 2012 and December 2019 were retrospectively included in this analysis. Patient characteristics were collected at the time of the index hospitalization. Using the Zoll® lifeVest® (ZOLL Medical Corporation, Chelmsford, MA, USA) network database, two separate investigators evaluated adherence to the WCD as well as arrhythmic events during WCD wear time.During 3680 wearing days (mean WCD wear time, 44 days) with a median daily wear time of 23.1 h, three arrhythmic events of relevance (sustained ventricular tachycardia, VT) occurred, one of which was sufficiently terminated by WCD shock. Another patient died from sudden cardiac death while pausing his WCD. Right bundle branch block correlated significantly with sustained VT occurrence (r = 0.3315; 95% CI -0.1265 to 0.3014; p = 0.0022). In 30 patients (36.1%) a cardioverter/defibrillator was implanted.In a real-life clinical setting, the use of WCD in patients at high risk for sudden cardiac death is effective and safe and adherence to the device is high. The event rate for VA was lower than in comparable patient cohorts. Adherence remains a crucial issue as one patient in the present series died while not wearing the device.HINTERGRUND: Frühere Studien belegen die Bedeutung des tragbaren Kardioverter/Defibrillators (WCD) für die wirksame und sichere Überbrückung eines temporären Risikos des plötzlichen Herztods (SCD) bei Patienten mit fortgeschrittener Herzinsuffizienz. Der prognostische Stellenwert einer solchen Therapie ist jedoch weiterhin umstritten.Wir untersuchten Adhärenz, Sicherheit und Effektivität der Kardioverter/Defibrillator-Weste im kardiologischen Versorgungsalltag einer Kohorte von Patienten mit hohem SCD-Risiko.Alle 83 zwischen April 2012 und Dezember 2019 in einer deutschen Klinik der Tertiärversorgung mit einem WCD versorgten Patienten wurden retrospektiv in diese Analyse eingeschlossen. Die Basischarakteristika wurden im Rahmen der Indexhospitalisierung erhoben. Die Auswertung von WCD-Adhärenz und arrhythmogenen Ereignissen während der WCD-Tragezeit erfolgte durch zwei unabhängige Untersucher anhand der Daten des LifeVest® Network der Fa. Zoll® (ZOLL Medical Corporation, Chelmsford, MA, USA).Während 3680 Tragetagen (mittlere WCD-Tragedauer 44 Tage) mit einer medianen täglichen Tragedauer von 23,1 h traten drei anhaltende ventrikuläre Tachykardien (VT) über 30 s Dauer auf. Davon konnte eine erfolgreich durch einen WCD-Schock terminiert werden. Ein anderer Patient erlag einem SCD, als er die Weste gerade nicht trug. Ein Rechtsschenkelblock korrelierte signifikant mit dem Auftreten einer anhaltenden VT (r = 0,3315; 95 %-Konfidenzintervall −0,1265 bis 0,3014; p = 0,0022). Bei 30 Patienten (36,1 %) wurde ein Kardioverter/Defibrillator implantiert.Die Anwendung des WCD in einem Hochrisikokollektiv für SCD unter klinischen Alltagsbedingungen ist sicher und effektiv, die Adhärenz der Patienten ist hoch. Die Rate an Arrhythmieereignissen war geringer als in vergleichbaren Patientenkollektiven. Die Adhärenz bleibt ein entscheidendes Problem, da ein Patient bei fehlender individueller Compliance einem SCD erlag.

Background COVID-19 comprises several severity stages ranging from oligosymptomatic disease to multi-organ failure and fatal outcomes. The mechanisms why COVID-19 is a mild disease in some patients and progresses to a severe multi-organ and often fatal disease with respiratory failure are not known. Biomarkers that predict the course of disease are urgently needed. The aim of this study was to evaluate a large spectrum of established laboratory measurements. Patients and Methods Patients from the prospective PULMPOHOM and CORSAAR studies were recruited and comprised 35 patients with COVID-19, 23 with conventional pneumonia, and 28 control patients undergoing elective non-pulmonary surgery. Venous blood was used to measure the serum concentrations of 79 proteins by Luminex multiplex immunoassay technology. Distribution of biomarkers between groups and association with disease severity and outcomes were analyzed. Results The biomarker profiles between the three groups differed significantly with elevation of specific proteins specific for the respective conditions. Several biomarkers correlated significantly with disease severity and death. Uniform manifold approximation and projection (UMAP) analysis revealed a significant separation of the three disease groups and separated between survivors and deceased patients. Different models were developed to predict mortality based on the baseline measurements of several protein markers. A score combining IL-1ra, IL-8, IL-10, MCP-1, SCF and CA-9 was associated with significantly higher mortality (AUC 0.929). Discussion Several newly identified blood markers were significantly increased in patients with severe COVID-19 (AAT, EN-RAGE, myoglobin, SAP, TIMP-1, vWF, decorin) or in patients that died (IL-1ra, IL-8, IL-10, MCP-1, SCF, CA-9). The use of established assay technologies allows for rapid translation into clinical practice., Graphical Abstract

Background Increased arterial stiffness (AS) has been described as a predictor of atrial fibrillation (AF). This study was performed to assess whether increased AS leads to a higher symptom burden in patients with AF. Methods One hundred sixty-two consecutive patients (104 male, 58 female) with diagnosed AF (paroxysmal or persistent) were enrolled. Symptoms most likely attributable to AF were quantified according to the Canadian Cardiovascular Society Severity of Atrial Fibrillation (SAF) scale. AS indices (aortic distensibility, cyclic circumferential strain, and aortic compliance) were characterized using transoesophageal echocardiography. Results The cohort was divided into asymptomatic to oligosymptomatic (SAF scale 0-1, n = 78 [48.1%]) and symptomatic (SAF scale ≥ 2, n = 84 [51.9%]) patients. Symptomatic patients tended to be younger (median, 75 [interquartile range (IQR) 67-80] vs 71 [65-79]; P = 0.047) and were more likely to be female (22 [28.2%] vs 36 [42.9%]; P = 0.052). Hypertension was more frequent in symptomatic patients. Aortic compliance indices each were reduced in symptomatic patients, most pronounced for aortic compliance (median, 0.05 [IQR 0.03-0.06] vs 0.04 [0.03-0.05] cm/mm Hg; P = 0.01) followed by cyclic circumferential strain (median, 0.09 [IQR 0.07-0.11] vs 0.07 [0.04-0.10]; P = 0.02) and aortic distensibility (10−3 mm Hg−1, median, 1.74 [IQR 1.34-2.24] vs 1.54 [1.12-2.08]; P = 0.03). Multivariable analysis revealed aortic compliance as an independent predictor for symptoms in patients with AF with an odds ratio of 2.6 (95% confidence interval, 1.2-3.4; P = 0.003). Conclusions AS contributes to a high symptom burden in patients with AF, emphasizing the prognostic role of AS in the early detection and prevention in patients with AF.

Lowering of low-density lipoprotein (LDL) cholesterol represents one of the most effective interventions in cardiovascular prevention. Besides the oral treatment with statins, ezetimibe and bempedoic acid, subcutaneously administered inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) have been established as further cornerstones of lipid-lowering treatment. The antibodies evolocumab and alirocumab are administered subcutaneously every 2-4 weeks and lower LDL cholesterol by around 60%, independent of pre-treatment with very good tolerability. Both drugs successfully reduced cardiovascular endpoints in large outcome trials. A novel principle of PCSK9 inhibition is RNA interference, which is exploited by the novel compound inclisiran. Inclisiran is a double-stranded modified RNA molecule, which neutralizes the mRNA of PCSK9 and thus inhibits PCSK9 protein synthesis intracellularly. Inclisiran only needs to be administered every 6 months. The cardiovascular outcome trial ORION‑4 is currently ongoing. In Germany, prescription of PCSK9 inhibitors is regulated by the decision of the Federal Joint Committee. Novel strategies to inhibit PCSK9 function are under development and include orally available drugs and animal experiment concepts on gene editing, which are in different states of evaluation.Die therapeutische Senkung des LDL(„low-density lipoprotein“)-Cholesterins ist einer der effektivsten Maßnahmen in der kardiovaskulären Prävention. Neben der oralen Therapie mit Statinen, Ezetimib und Bempedoinsäure haben sich subkutan applizierte Inhibitoren der Proproteinkonvertase Subtilisin/Kexin Typ 9 (PCSK9) als weitere Säule der lipidsenkenden Therapie etabliert. Die alle 2 bis 4 Wochen subkutan zu verabreichenden Antikörper Evolocumab und Alirocumab senken das LDL-Cholesterin unabhängig von der Vorbehandlung um rund 60 % bei sehr guter Verträglichkeit. Für beide Wirkstoffe liegen positive Endpunktstudien vor. Ein neues Prinzip zur PCSK9-Inhibition ist die RNA-Interferenz, welche mit dem Wirkstoff Inclisiran genutzt wird. Bei Inclisiran handelt es sich um ein doppelsträngiges modifiziertes RNA-Molekül, welches die mRNA von PCSK9 neutralisiert und damit die PCSK9-Proteinsynthese intrazellulär hemmt. Inclisiran muss nur halbjährlich appliziert werden. Die Endpunktstudie ORION‑4 läuft gegenwärtig. Die Verschreibung von PCSK9-Hemmern ist in Deutschland durch einen Beschluss des Gemeinsamen Bundesausschusses reglementiert. Neue Strategien zur PCSK9-Hemmung sind in Entwicklung und umfassen u. a. oral verfügbare Wirkstoffe und tierexperimentelle Konzepte zur Gentherapie, welche sich in unterschiedlichen Stadien der Prüfung befinden.

There are no outcome studies for coronavirus disease 2019 (COVID-19) survivors one year after hospital discharge in Germany.This retrospective cohort study included all patients with polymerase chain reaction (PCR)-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hospitalized in the departments of internal medicine of the Klinikum Saarbrücken, a tertiary care hospital, between March 15 and December 31, 2020. A telephone interview with survivors was conducted at least 12 months after discharge. The interview was initiated with an open-ended question whether the patient had fully recovered from the disease. In the event of a subjective incomplete recovery, the patient was prompted to report any continuous or frequent symptoms that had not occurred prior to COVID-19. Finally, independent of the open-ended question response, all patients were asked closed questions which addressed new symptom onset of persistent fatigue, cognitive dysfunction, headache, muscle and joint pain following COVID-19.In all, 235 survivors were contacted and 162 could be included in the analysis. In 55 of 162 interviews (34.0%) at least one persistent COVID-19 symptom (PCS) was spontaneously reported. Four of 55 survivors with PCS reported five additional symptoms on the closed questions. One survivor, who responded positively to the open-ended question, reported new onset PCS in response to the closed questions. Physical fatigue (24.7%), cognitive dysfunction (14.8%), shortness of breath (8.6%), muscle and joint pain (6.8%) and headache (6.2%) were the most frequently reported PCS.Despite an interview technique aimed to reduce attribution bias by patients, one third of COVID-19 inpatient survivors report PCS one year after hospitalization. The complete article is written in English.HINTERGRUND: In Deutschland wurden bisher keine Studien über den Gesundheitszustand von Überlebenden einer „coronavirus disease 2019“ (COVID-19) ein Jahr nach Entlassung aus der stationären Behandlung publiziert.Diese retrospektive Kohortenstudie schloss alle Patienten mit Polymerase-Kettenreaktions(PCR)-Nachweis des „severe acute respiratory syndrome coronavirus 2“ (SARS-CoV-2) ein, die vom 15. März bis 31. Dezember 2020 in den internistischen Abteilungen des Klinikums Saarbrücken, einem Krankenhaus der Maximalversorgung, behandelt worden waren. Ein Telefoninterview mit den Überlebenden wurde frühestens 12 Monate nach stationärer Entlassung durchgeführt. Das Interview begann mit der offenen Frage, ob der Patient sich vollständig von COVID-19 erholt hatte. Im Falle der Angabe einer unvollständigen Erholung wurde der Patient gebeten, alle anhaltenden oder häufigen Beschwerden zu schildern, die er vor COVID-19 nicht gehabt hatte. Danach wurden – unabhängig von der Antwort auf die Eingangsfrage – geschlossene Fragen nach einem neuen Auftreten von anhaltender Müdigkeit, geistigen Problemen sowie Kopf- und Gliederschmerzen nach COVID-19 gestellt.Insgesamt 235 Überlebende wurden kontaktiert und 162 konnten in die Analyse eingeschlossen werden. In 55 von 162 Interviews (34,0 %) wurde mindestens ein anhaltendes COVID-19-Symptom („persistent COVID-19 symptom“ [PCS]) spontan berichtet. Vier von 55 Überlebenden mit PCS gaben 5 weitere PCS bei den geschlossenen Fragen an. Ein Überlebender, der die Eingangsfrage bejaht hatte, berichtete ein neu aufgetretenes PCS bei den geschlossenen Fragen. Anhaltende Müdigkeit (24,7 %), geistige Probleme (14,8 %), Atemnot (8,6 %), Gelenkschmerzen (6,8 %) und Kopfschmerzen (6,2 %) waren die häufigsten spontan berichteten PCS.Trotz einer Interviewtechnik, die darauf ausgerichtet war, eine Fehlattribution von Symptomen zu COVID-19 durch die Patienten zu vermeiden, berichtete ein Drittel der stationär behandelten Überlebenden über PCS 12 Monate nach stationärer Behandlung mit COVID-19. Das komplette Beitrag ist in englischer Sprache abgefasst.

BACKGROUND There were gaps between guidelines and practice when surgery was the only treatment for aortic stenosis (AS). OBJECTIVES This study analyzed the decision to intervene in patients with severe AS in the EORP VHD (EURObservational Research Programme Valvular Heart Disease) II survey. METHODS Among 2,152 patients with severe AS, 1,271 patients with high-gradient AS who were symptomatic fulfilled a Class I recommendation for intervention according to the 2012 European Society of Cardiology guidelines; the primary end point was the decision for intervention. RESULTS A decision not to intervene was taken in 262 patients (20.6%). In multivariate analysis, the decision not to intervene was associated with older age (odds ratio [OR]: 1.34 per 10-year increase; 95% CI: 1.11 to 1.61; P = 0.002), New York Heart Association functional classes I and II versus III (OR: 1.63; 95% CI: 1.16 to 2.30; P = 0.005), higher age adjusted Charlson comorbidity index (OR: 1.09 per 1-point increase; 95% CI: 1.01 to 1.17; P = 0.03), and a lower transaortic mean gradient (OR: 0.81 per 10-mm Hg decrease; 95% CI: 0.71 to 0.92; P < 0.001). During the study period, 346 patients (40.2%, median age 84 years, median EuroSCORE II [European System for Cardiac Operative Risk Evaluation II] 3.1%) underwent transcatheter intervention and 515 (59.8%, median age 69 years, median EuroSCORE II 1.5%) underwent surgery. A decision not to intervene versus intervention was associated with lower 6-month survival (87.4%; 95% CI: 82.0 to 91.3 vs 94.6%; 95% CI: 92.8 to 95.9; P < 0.001). CONCLUSIONS A decision not to intervene was taken in 1 in 5 patients with severe symptomatic AS despite a Class I recommendation for intervention and the decision was particularly associated with older age and combined comorbidities. Transcatheter intervention was extensively used in octogenarians. (J Am Coll Cardiol 2021;78:2131-2143) (c) 2021 by the American College of Cardiology Foundation.

Background Cardiooncology is a relatively new subspeciality, investigating the side effects of cytoreductive therapies on the cardiovascular (CV) system. Gender differences are well known in oncological and CV diseases, but are less elucidated in cardiooncological collectives. Methods Five hundred and fifty-one patients (278 male, 273 female) with diagnosed cancer who underwent regular cardiological surveillance were enrolled in the ‘MAnnheim Registry for CardioOncology’ and followed over a median of 41 (95% confidence interval: 40–43) months. Results Female patients were younger at the time of first cancer diagnosis [median 60 (range 50–70) vs. 66 (55–75), P = 0.0004], while the most common tumour was breast cancer (49.8%). Hyperlipidaemia was more often present in female patients (37% vs. 25%, P = 0.001). Male patients had a higher cancer susceptibility than female patients. They suffered more often from hypertension (51% vs. 67%, P = 0.0002) or diabetes (14% vs. 21%, P = 0.02) and revealed more often vitamin D deficiency [(U/l) median 26.0 (range 17–38) vs. 16 (9–25), P = 0.002] and anaemia [(g/dl) median 11.8 (range 10.4–12.9) vs. 11.7 (9.6–13.6), P = 0.51]. During follow-up, 140 patients died (male 77, female 63; P = 0.21). An increased mortality rate was observed in male patients (11.4% vs. 14%, P = 0.89), with even higher mortality rates of up to 18.9% vs. 7.7% (P = 0.02) considering tumours that can affect both sexes compared. Conclusions Although female patients were younger at the time of first cancer diagnosis, male patients had both higher cancer susceptibility and an increased mortality risk. Concomitant CV diseases were more common in male patients.

Epidemiological and clinical studies have shown a relevant association between heart rate and cardiovascular mortality. Experimental studies identified vascular effects of heart rate reduction with the If channel inhibitor ivabradine. Therefore, the effects of heart rate reduction on endothelial function and indices of arterial stiffness were examined in patients with stable coronary artery disease in a prospective, placebo-controlled clinical crossover study.Twenty-three patients (18 men and 5 women) with a resting heart rate (HR) of at least 70 beats per minute (bpm) and stable coronary artery disease were enrolled in this study. In a cross-over design, all patients were treated with ivabradine (Iva, 7.5 mg b.i.d.) and placebo for 6 months each. Iva reduced heart rate by 11.4 bpm (Iva 58.8 ± 8.2 bpm vs. placebo 70.2 ± 8.3 bpm, P 0.0001). Augmentation index (AIx75), carotid-femoral pulse wave velocity (cfPWV) and central aortic blood pressure were measured using applanation tonometry (SphygmoCor). HRR by Iva increased AIx75 by 12.4% (Iva 24.3 ± 10.5% vs. placebo 21.3 ± 10.1%, P 0.05) and reduced cfPWV by 14.1% (Iva 6.3 ± 1.7 m/s vs. placebo 7.3 ± 1.4 m/s, P 0.01). Iva increased mean central blood pressure by 7.8% (Iva 107.5 ± 15.4 mmHg vs. placebo 99.1 ± 12.2 mmHg, P 0.001). Endothelial function was determined measuring the flow-mediated vasodilation (FMD) of the brachial artery. HRR by Iva increased FMD by 18.5% (Iva 7.3 ± 2.2% vs. placebo 6.0 ± 2.0%, P 0.001). Aortic distensibility was characterized by MRI. HRR by Iva increased aortic distensibility by 33.3% (Iva 0.003 ± 0.001/mmHg vs. placebo 0.002 ± 0.010/mmHg, P 0.01) and circumferential cyclic strain by 37.1% (Iva 0.062 ± 0.027 vs. placebo 0.039 ± 0.018, P 0.0001).Heart rate reduction with Iva increased endothelium-dependent vasodilation and reduced arterial stiffness in patients with stable CAD. These findings corroborate and expand the results collected in experimental studies and indicate the importance of heart rate as a determinant of vascular function.

Objectives We sought to assess central hemodynamic effects in 23 patients (18 male, 5 female) with a resting heart rate (HR) of ≥70 beats per minute (bpm) and chronic coronary syndrome after long-term ivabradine therapy (6 months) by cardiac magnetic resonance (CMR). Methods and results In a cross-over design, all patients were treated with ivabradine (Iva, 7.5 mg bid) and placebo for 6 months each. CMR was performed three times (at baseline, after 6 and 12 months) to determine left ventricular (LV) function parameters, including end-diastolic and end-systolic volumes (EDVi, ESVi), stroke volume (SVi) and ejection fraction (EF) as well as volume-time curve (VTC) parameters, including peak ejection rate (PER), peak ejection time (PET), peak filling rate (PFR), peak filling time from ES (PFT), peak ejection rate normalized to EDV (PER/EDV) and peak filling rate normalized to EDV (PFR/EDV) for global LV function (systolic and diastolic) assessment. Flow measurements of the ascending aorta were performed with phase-contrast velocity imaging. Treatment with Iva led to a HR reduction of 11.4 bpm (Iva 58.8±8.2 bpm vs placebo 70.2±8.3 bpm, p Conclusion Systolic LV function was unaffected by treatment with Iva, while the filling during diastole was significantly improved. While medium and maximum aortic flow were not affected by Iva, mean velocity was significantly reduced. Aortic distensibility as surrogate parameter for arterial stiffness was significantly correlated to aortic mean velocity. This study confirms the underlying physiological principle of the If-current inhibitor Ivabradine. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): This work was supported by the Deutsche Herzstiftung (German Heart Foundation) (F/14/11 to F.C.) and the Deutsche Forschungsgemeinschaft (DFG KFO 196 to U.L., S.H.S and M.B. and SFB TTR 219, S-01 to M.B.). The Saarland University Medical Center has received an unrestricted grant from Servier (France).

Background and purpose Oral anticoagulation prevents thromboembolism in atrial fibrillation. Factor Xa inhibitors, like edoxaban, are known to reduce inflammation and proliferation of smooth muscle cells, while vitamin K antagonism can cause vascular calcific damage. The influence of edoxaban compared to warfarin on vascular remodeling, atherosclerosis and arteriogenesis is unknown. Experimental approach Apolipoprotein E knockout (ApoE −/−) mice were fed cholesterol-rich diet alone (control, co), with warfarin+vitamin K1 (warf) or with edoxaban (Edo) for 8 weeks. After 6 weeks, femoral artery ligation was performed. Key results There was no difference in hind-limb perfusion restoration between the three groups after 14 days (Co 0.36 ± 0.05 vs. Warf 0.39 ± 0.09 (p = .39), Co vs. Edo 0.51 ± 0.06 (p = .089), Warf vs. Edo (p = .83)) after ligation. Immuno-histologically, there was no difference in smooth muscle cell count in both hindlimbs between the three groups or in the amount of perivascular macrophages in collateral-bearing hindlimb tissue. Edoxaban showed the lowest amount of plaque tissue in the aortic sinus tissue (Co 74 ± 11% vs. Edo 62 ± 12% (p = .024), Co vs. Warf 69 ± 14% (p = .30), Edo vs. Warf (p = .14)) as well as the least amount of fibrosis (Co 3.1 ± 0.9% vs. Edo 1.7 ± 0.6% (p = .027), Co vs. Warf 4.1 ± 0.7% (p = .081), Edo vs. Warf (p Conclusion and implications These data suggest that treatment with edoxaban unlike warfarin prevents vascular maladaptive remodeling, which may be clinically important.

Objectives: We assessed left ventricular (LV) function and central hemodynamic effects in patients with a heart rate (HR) at rest of ≥70 beats per minute (bpm) and chronic coronary syndrome (CCS) after long-term treatment with ivabradine compared to placebo by cardiac magnetic resonance (CMR) imaging. Methods and results: In a randomized, double-blinded, prospective cross-over design, 23 patients (18 male, 5 female) were treated with ivabradine (7.5 mg bid) or placebo for 6 months. CMR imaging was performed at baseline and after 6 and 12 months to determine LV functional parameters.Mean resting HR on treatment with ivabradine was 58 ± 8.2 bpm and 70.2 ± 8.3 bpm during placebo (p

Florian Custodis,1 Franziska Rohlehr,1 Angelika Wachter,1 Michael Böhm,1 Martin Schulz,2 Ulrich Laufs1 1Department of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, Saarland University Medical Center, Homburg/Saar, 2Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany Background: A substantial aspect of health literacy is the knowledge of prescribed medication. In chronic heart failure, incomplete intake of prescribed drugs (medication non-adherence) is inversely associated with clinical prognosis. Therefore, we assessed medication knowledge in a cohort of patients with decompensated heart failure at hospital admission and after discharge in a prospective, cross-sectional study.Methods: One hundred and eleven patients presenting at the emergency department with acute decompensated heart failure were included (mean age 78.4±9.2, 59% men) in the study. Patients’ medication knowledge was assessed during individual interviews at baseline, course of hospitalization, and 3 months after discharge. Individual responses were compared with the medical records of the referring general practitioner.Results: Median N-terminal prohormone of brain natriuretic peptide plasma concentration in the overall population at baseline was 4,208 pg/mL (2,023–7,101 pg/mL [interquartile range]), 20 patients died between the second and third interview. The number of prescribed drugs increased from 8±3 at baseline to 9±3 after 3 months. The majority of patients did not know the correct number of their drugs. Medication knowledge decreased continuously from baseline to the third interview. At baseline, 37% (n=41) of patients stated the correct number of drugs to be taken, whereas only 18% (n=16) knew the correct number 3 months after discharge (P=0.008). Knowledge was inversely related to N-terminal prohormone of brain natriuretic peptide levels.Conclusion: Medication knowledge of patients with acute decompensated heart failure is poor. Despite care in a university hospital, patients’ individual medication knowledge decreased after discharge. The study reveals an urgent need for better strategies to improve and promote the knowledge of prescribed medication in these very high-risk patients. Keywords: medication knowledge, hospitalization, chronic heart failure, health literacy&nbsp

Die 2‑ oder 4‑wochentliche subkutane Therapie mit den neu zugelassenen Antikorpern Alirocumab und Evolocumab zur Hemmung von PCSK9 (Proproteinkonvertase Subtilisin/Kexin Typ 9) senkt das LDL-C („Low-density-lipoprotein“-Cholesterin) zusatzlich zu Statinen und Ezetimib um 50–60 %. Die Therapie ist gut vertraglich. Die Ergebnisse der grosen randomisierten Studien zum Einfluss auf kardiovaskulare Ereignisse und zur Beurteilung der Sicherheit liegen noch nicht vor, sie werden 2016 bis 2018 erwartet. Daher kommen aktuell (Fruhjahr 2016) insbesondere Patienten mit hohem kardiovaskularen Risiko und hohem LDL-C trotz Einsatz einer maximal vertraglichen oralen lipidsenkenden Therapie fur eine PCSK9-Hemmung in Frage. Dies betrifft z. B. ausgewahlte Patienten mit statinassoziierten Muskelbeschwerden (SAMS) und Patienten mit familiarer Hypercholesterinamie.

Background Myocardial calcification after prolonged highly dosed catecholamine treatment has been described experimentally. Here, we demonstrate myocardial calcifications by high-dose catecholamine treatment leading to chronic heart failure in patients. Case summary A 62-year-old Caucasian woman presented with central pulmonary embolism, developing acute heart failure, and cardiogenic shock. Twenty-six days of high-dose norepinephrine treatment had to be administered to maintain circulation. After 74 days of intensive care treatment, the patient fortunately recovered but was readmitted to emergency ward because of dyspnoea and congestion. Computed tomography pulmonary angiography ruled out recurrence of pulmonary embolism, but depicted massive intramural cardiac calcifications, which were not present before treatment. Coronary angiography showed normal coronary arteries, and myocardial biopsy excluded infectious myocarditis. There was no evidence for sarcoidosis, thyroid disease, tuberculosis, or hyperparathyroidism. Oral heart failure treatment was initiated and at the 7 week follow-up the patient remained symptomatic with New York Heart Association functional Class III, while right and left ventricular function had recovered. Discussion Prolonged activation of the heart by catecholamines leading to myocardial calcifications has first been examined experimentally by Fleckenstein et al. Herein, we are able to show, that this can occur in clinical situations. Careful dosing of catecholamines and early use of non-catecholamine-based haemodynamic support is recommended to avoid consecutive impairment of heart function and heart failure.

Der Begriff der „LDL-Hypothese“ wird haufig verwendet um den Zusammenhang von LDL Cholesterin (LDL-C) und kardiovaskularen Ereignissen zu beschreiben. Im Hinblick auf aktuelle Studienergebnisse stellt sich die Frage, inwieweit dieser Terminus noch adaquat ist. Vor dem Hintergrund der Daten zur kausalen Bedeutung des LDL fur die molekulare und zellulare Pathogenese der Atherosklerose, der Epidemiologie und der klaren genetischen Assoziation von LDL-C und Herzinfarktrisiko sowie der grosen Statin-Studien sowie dem Beleg einer Ereignis-Reduktion durch eine nicht Statin-vermittelte LDL Senkung in der IMPROVE-IT Studie erscheint der Terminus „Hypothese“ uberholt und der Begriff „LDL-Kausalitat“ adaquat.

Abstract— Elevated systolic blood pressure (SBP) correlates to cognitive decline and incident dementia. The effects of heart rate (HR), visit to visit HR variation, and visit to visit SBP variation are less well established. Patients without preexisting cognitive dysfunction (N=24 593) were evaluated according to mean SBP, SBP visit to visit variation (coefficient of variation [standard deviation/mean×100%], CV), mean HR, and visit to visit HR variation (HR-CV) in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial and the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease. Cognitive function was assessed with mini mental state examination. Cognitive dysfunction (fall in mini mental state examination ≤24 points), important cognitive decline (drop of ≥5 points), and cognitive deterioration (drop of >1 point per year or decline to < 24 points) were assessed. SBP and HR were measured over 10.7±2.2 (mean±SD) visits. Mean SBP, mean HR, and SBP-CV were associated with cognitive decline, dysfunction, and deterioration (all P P =0.0030) and mean HR ( P =0.0008) remained predictors for cognitive dysfunction (odds ratios [95% confidence intervals], 1.32 [1.10–1.58] for 5th versus 1st quintile of SBP-CV and 1.40 [1.18–1.66] for 5th versus 1st quintile of mean HR). Similar effects were observed for cognitive decline and deterioration. SBP-CV and mean HR showed additive effects. In conclusion, SBP-CV and mean HR are independent predictors of cognitive decline and cognitive dysfunction in patients at high CV risk. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT 00153101.

Die Herzfrequenz ist eine einfache klinische Variable mit weitreichender prognostischer Bedeutung. Eine unter Ruhebedingungen erhohte Herzfrequenz ist mit einem erhohten kardiovaskularen Risiko verknupft. Daten epidemiologischer Studien demonstrieren sowohl fur Personen ohne bekannte kardiovaskulare Erkrankungen sowie fur Individuen mit bestehenden kardiovaskularen Erkrankungen wie arterieller Hypertonie, koronarer Herzerkrankung (KHK) und chronischer Herzinsuffizienz eine relevante Assoziation zwischen der Hohe der Herzfrequenz und der mittleren Uberlebenszeit. Wahrend eine gezielte medikamentose Herzfrequenzreduktion im Rahmen der Primarpravention bislang keine Rolle spielt, ist sie bei Patienten mit KHK und chronischer Herzinsuffizienz von wesentlicher symptomatischer und prognostischer Bedeutung. Fur die Herzinsuffizienz und moglicherweise auch die KHK ist die Herzfrequenz daruber hinaus als unabhangiger Risikofaktor anzusehen. Demnach weisen die Leitlinien eine Reduktion der Herzfrequenz als Therapieziel der medikamentosen Behandlung aus.

Heart rate was proposed as an emergent cardiovascular (CV) risk factor. Previous studies have shown associations between increased heart rate and CV risk in various populations. We aimed to evaluate the prognostic relevance of heart rate in a large contemporaneous medically optimized cohort of patients with stable chronic CV disease. In a post hoc analysis of the ONTARGET/TRANSCEND trials, we evaluated associations between baseline and average heart rate in trial with CV risk in 31, 531 patients followed for a median of 5 years. The primary outcome, major vascular events (MVE), was a composite of CV death, myocardial infarction (MI), stroke, and congestive heart failure (CHF). Pre-specified secondary outcomes included all-cause death and the individual components of the primary outcome. Associations between heart rate and outcomes were computed with heart rate as a continuous variable, baseline heart rate >70 vs ≤70 bpm, and across heart rate quintiles, adjusting for other markers of risk, beta-blocker and non-dihydropyridine calcium channel blocker use. For each 10 bpm increase in baseline and average heart rate, we observed a significant increase in risk of MVE, CV death, CHF and all-cause death. There was a continuous relationship between MVE and baseline and, more importantly, average in-trial heart rate, with no observed threshold. MVE, CV death, stroke, CHF, and all-cause death increased across heart rate quintiles. There was no association between MI and HR. Results were consistent in clinically relevant subgroups. There were modest but significant improvements in C-statistic and in statistical measures of model calibration for models that included heart rate for MVE, CV death, CHF and all-cause death. This large study examined and quantitated associations between heart rate and CV events in a contemporary medically optimized population with stable CV disease. Resting and, in particular, in-trial average heart rate are independently associated with significant increases in CV events and all-cause death.

Heart rate is a predictor of cardiovascular and all-cause mortality in the general population and in patients with cardiovascular disease. Increased resting heart rate multiplies risk and interferes at all stages of the cardiovascular disease continuum initiating from endothelial dysfunction and continuing via atherosclerotic lesion formation and plaque rupture to end-stage cardiovascular disease. As a therapeutic target, heart rate is accessible via numerous pharmacological interventions. The concept of selective heart rate reduction by the I(f) current inhibitor ivabradine provides an option to intervene effectively along the chain of events and to define the specific and prognostic role of heart rate for patients with coronary artery disease and heart failure. Future interventional studies will further clarify the significance of heart rate and targeted heart rate reduction for primary and secondary prevention in cardiovascular and cerebrovascular events.

High resting heart rate (RHR) predicts cardiovascular outcomes in patients with vascular disease and heart failure. We evaluated the prognostic value of RHR in a large contemporary population-based, prospective cohort of individuals without known coronary artery disease. Resting heart rate (RHR) was determined in 4091 individuals (mean age 59.2 ± 7.7; 53 % women) from the Heinz Nixdorf RECALL study, of whom, 3348 were free of heart rate lowering medication. During 10.5 years of follow-up (median), 159 (3.9 %) individuals developed a coronary event and 398 (9.7 %) died of any cause. Persons without any event (n = 3603) had similar heart rates as persons with coronary events (69.5 ± 11 versus 69.9 ± 11 bpm, p = 0.51) but lower heart rates than persons who died (72.3 ± 13 bpm, p

Aims In diabetes mellitus, heart failure with preserved ejection fraction (HFPEF) is a significant comorbidity. No therapy is available that improves cardiovascular outcomes. The aim of this study was to characterize myocardial function and ventricular-arterial coupling in a mouse model of diabetes and to analyse the effect of selective heart rate (HR) reduction by I f-inhibition in this HFPEF-model. Methods and results Control mice, diabetic mice ( db/db ), and db/db mice treated for 4 weeks with the If-inhibitor ivabradine ( db/db -Iva) were compared. Aortic distensibility was measured by magnetic resonance imaging. Left ventricular (LV) pressure–volume analysis was performed in isolated working hearts, with biochemical and histological characterization of the cardiac and aortic phenotype. In db/db aortic stiffness and fibrosis were significantly enhanced compared with controls and were prevented by HR reduction in db/db -Iva. Left ventricular end-systolic elastance ( E es) was increased in db/db compared with controls (6.0 ± 1.3 vs. 3.4 ± 1.2 mmHg/µL, P < 0.01), whereas other contractility markers were reduced. Heart rate reduction in db/db -Iva lowered E es (4.0 ± 1.1 mmHg/µL, P < 0.01), and improved the other contractility parameters. In db/db active relaxation was prolonged and end-diastolic capacitance was lower compared with controls (28 ± 3 vs. 48 ± 8 μL, P < 0.01). These parameters were ameliorated by HR reduction. Neither myocardial fibrosis nor hypertrophy were detected in db/db , whereas titin N2B expression was increased and phosphorylation of phospholamban was reduced both being prevented by HR reduction in db/db -Iva. Conclusion In db/db , a model of HFPEF, selective HR reduction by I f-inhibition improved vascular stiffness, LV contractility, and diastolic function. Therefore, I f-inhibition might be a therapeutic concept for HFPEF, if confirmed in humans.

OBJECTIVE: A critical problem in cardiovascular MRI in small rodents is adjusting the sequence acquisition to the high heart and respiratory rates. The aim of this study was to compare a retrospectively self-gated fast low angle shot navigator (RSG-FLASH) sequence with a conventional prospectively triggered (PT-FLASH) sequence for cine imaging of the ascending aorta in mice at 9.4 T. MATERIAL AND METHODS: Ten C57/BL6 mice were examined with a horizontal bore 9.4 Tesla MRI animal scanner using a dedicated 2 × 2 phased-array surface coil. We acquired a RSG-FLASH sequence (RSG-FLASH sequences (repetition time (TR) / echo time (TE) = 6.5/2.5 ms, flip angle (FA) = 10 degrees, field of view (FOV) = 2 × 2 cm, matrix = 384 × 384, slice thickness = 1 mm, 25 movie frames) perpendicular to the ascending aorta using the IntraGate technique. At the same position, we performed a PT-FLASH sequence (TR/TE = 6.5/2.1 ms, FA = 10 degrees, FOV = 2 × 2 cm, matrix = 384 × 384, slice thickness = 1 mm) in which the maximum number of movie frames had to be adjusted to the interval between two R-peaks (RR interval) of the electrocardiogram (ECG) with: number of frames = RR interval / TR." Cross-sectional vessel areas at end-systole (AES) and end-diastole (AED) were measured to determine the aortic strain (ΔA = (AES-AED)/AED). Two blinded readers rated the sequences for presence of flow and trigger artifacts and their influence on the depiction of the blood/vessel-wall interface. Irregularities in displaying the cardiac cycle and the overall suitability of the sequence for aortic strain evaluation were assessed using a 5-level ordinal scale. Statistical differences were analyzed using Student t test and Wilcoxon signed rank test (P < 0.05). Intra- and interobserver variability was evaluated using Bland-Altman analyses. RESULTS: No significant differences were noted between techniques regarding the measured vessel areas (AED: P = 0.07, AES: P = 0.34), ΔA: P = 0.1). Similarly, there were no significant differences in heart (P = 0.06) and respiratory (P = 0.24) rates. The acquisition time for RSG-FLASH sequence was significantly shorter (P = 0.04). Significantly fewer flow and trigger artifacts were noted by both readers with the RSG-FLASH sequence. Likewise, both readers considered the RSG-FLASH sequence to be superior for depiction of the blood/vessel-wall interface. The RSG-FLASH sequence was also rated superior regarding irregularities in displaying the cardiac cycle and in terms of overall suitability for evaluation of AED, AES, and aortic strain (P < 0.05 each). CONCLUSION: RSG-FLASH is preferable for cine imaging of the aorta. It provides the same quantitative data as PT-FLASH cine imaging but is less prone to flow and trigger artifacts. RSG-FLASH permits more homogeneous depiction of the cardiac cycle and is faster than the PT-FLASH sequence. PT-FLASH is more prone to misregistration of the respiratory cycle or the ECG by the external monitoring device used for acquisition. This effect may be even more pronounced in animals with disease models that are less stable in terms of heart and respiration rate during anesthesia.

Background: Impaired vascular compliance is associated with cardiovascular mortality. The effects of heart rate on vascular compliance are unclear. Therefore, we characterized effects of heart rate reduction (HRR) by I(f) current inhibition on aortic compliance and underlying molecular mechanisms in apolipoprotein E-deficient (ApoE–/–) mice. Methods: ApoE–/– mice fed a high-cholesterol diet and wild-type (WT) mice were treated with ivabradine (20 mg/kg/d) or vehicle for 6 weeks. Compliance of the ascending aorta was evaluated by MRI. Results: Ivabradine reduced heart rate by 113 ± 31 bpm (∼19%) in WT mice and by 133 ± 6 bpm (∼23%) in ApoE–/– mice. Compared to WT controls, ApoE–/– mice exhibited reduced distensibility and circumferential strain. HRR by ivabradine increased distensibility and circumferential strain in ApoE–/– mice but did not affect both parameters in WT mice. Ivabradine reduced aortic protein and mRNA expression of the angiotensin II type 1 (AT1) receptor and reduced rac1-GTPase activity in ApoE–/– mice. Moreover, membrane translocation of p47phox was inhibited. In ApoE–/– mice, HRR induced anti-inflammatory effects by reduction of aortic mRNA expression of IL-6, TNF-alpha and TGF-beta. Conclusion: HRR by ivabradine improves vascular compliance in ApoE–/– mice. Contributing mechanisms include downregulation of the AT1 receptor, attenuation of oxidative stress and modulation of inflammatory cytokine expression.

Die Herzfrequenz ist ein kardiovaskularer Risikoindikator. Insbesondere bei Patienten mit Herzinsuffizienz und moglicherweise auch bei koronarer Herzerkrankung ist eine erhohte Ruhe-Herzfrequenz als unabhangiger Risikofaktor anzusehen. Klinische und experimentelle Arbeiten weisen darauf hin, dass die Herzfrequenz selbst direkte Wirkungen auf strukturelle und funktionelle Eigenschaften des Herz-Kreislauf-Systems, v. a. auf das Gefassystem, ausubt. Die Daten der SHIFT-Studie belegen den Stellenwert der Herzfrequenz als Risikofaktor und Therapieansatz bei Patienten mit chronischer Herzinsuffizienz: Zusatzlich zu einer leitliniengerechten medikamentosen Therapie reduzierte Ivabradin die Haufigkeit von Klinikeinweisungen aufgrund einer klinischen Verschlechterung und reduzierte zudem herzinsuffizienzbedingte Todesfalle. Die Daten der BEAUTIFUL-Studie zeigen, dass eine Herzfrequenz von ≥70 Schlagen pro Minute bei Patienten mit einer ischamischen Kardiomyopathie das Risiko fur koronare Ereignisse erhoht.

Elevated Triglyceride levels are associated with increased risk for atherosclerotic disease and additional vascular risk factors such as obesity, hypertension and impaired glucose tolerance. To estimate the individual cardiovascular risk of a patient with elevated triglycerides LDL- and HDL-cholesterol levels, concomitant diseases, composition of triglyceride rich lipoproteins and a family history for premature coronary heart disease are important. Primary goals for the management of hypertriglyceridemia are a reduction of cardiovascular risk and prevention of triglyceride associated complications such as the chylomicronemia syndrome. The basis of treatment are lifestyle changes: dietary intervention, alcohol avoidance, regular physical activity, weight loss and smoking cessation to modify risk factors. If triglyceride levels can not be sufficiently reduced by lifestyle intervention pharmacotherapy (nicotinic acid, fibrates and omega-3-acid ethyl esters) is indicated. Beyond reduction of triglyceride levels optimization of non-HDL-cholesterol by statin treatment is warranted to reduce vascular risk.

Background and Purpose— Chronic stress is associated with increased stroke risk. However, the underlying pathophysiological mechanisms are poorly understood. We examined the effects of chronic stress on endothelial function and ischemic brain injury in a mouse model. Methods— 129/SV mice were treated with glucocorticoid receptor antagonist mifepristone (25 mg kg −1 /d) or vehicle and exposed to 28 days of chronic stress consisting of exposure to rat, restraint stress, and tail suspension. Heart rate and blood pressure were continuously recorded by telemetry. Endothelial nitric oxide synthase mRNA and protein expression as well as superoxide production and lipid hydroperoxides were quantified. Endothelium-dependent vasorelaxation was measured in aortic rings. Ischemic lesion volume was quantified after 30 minutes filamentous middle cerebral artery occlusion and 72 hours reperfusion. Results— Chronic stress caused a significant increase in heart rate, impaired endothelium-dependent vasorelaxation, increased superoxide production, and reduced aortic and brain endothelial nitric oxide synthase levels. Animals exposed to chronic stress showed major increases in ischemic lesion size. These deleterious effects of stress were completely reversed by treatment with mifepristone. Conclusions— Chronic stress increases stroke vulnerability likely through endothelial dysfunction, which can be reversed by a glucocorticoid receptor antagonist.

This article provides information and commentaries on trials which were presented at Clinical Trial Updates and Hotline Sessions presented at the Scientific Sessions 2007 of the American Heart Association in Orlando, Florida. The comprehensive summaries have been generated from the oral presentations and the webcasts of the American Heart Association. Most reports have not been published as full papers and therefore have to be considered as preliminary data, as the analysis may change in the final publications. The following papers are discussed: TRITON TIMI-38, EVA-AMI, BRIEF-PCI, RACE, MASS Stent, HF-ART, STITCH, CORONA, ILLUMINATE, CORE-64, OAT Substudy, AFCHF, MASCOT, RETHINQ, MASTER I, POISE, COUMA-GEN, HIJ-CREATE, PROVIDENCE I, CAUSMIC, IC-BMC, IC/IM BMCs.

Objectives We aimed to study the role of Rac1 GTPase in atrial fibrillation (AF). Background The signal transduction associated with AF is incompletely understood. We hypothesized that activation of Rac1 GTPase contributes to the pathogenesis of AF via activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and production of reactive oxygen species. Methods Old mice with cardiac-specific overexpression of constitutively active V12Rac1 (RacET) were compared with wild-type (WT) and WT undergoing transaortic constriction (TAC). In addition, samples of human left atrial appendages were analyzed in patients with sinus rhythm (SR) compared with patients with permanent AF matched for atrial diameter. Results At age 16 months, 75% of RacET but no WT or TAC mice showed AF. Treatment of RacET with statins for 10 months did not alter weight or fibrosis of atria or ventricles but decreased cardiac Rac1 and NADPH oxidase activity and reduced the incidence of AF by 50%. The left atria of patients with AF showed increased fibrosis, up-regulation of NADPH oxidase activity, a 4-fold increase of Rac1 total protein and membrane expression as well as up-regulation of Rac1 activity. Conclusions Chronic cardiac overexpression of Rac1 represents a novel mouse model for AF. Rac1 GTPase contributes to the pathogenesis of AF and identifies a target for the prevention and treatment of AF.

The term "LDL-Hypothesis" is frequently used to describe the association between LDL cholesterol (LDL-C) and cardiovascular outcomes. In the light of recent results of randomized trials the question arises whether the term hypothesis is still adequate. Considering the causal importance of LDL for the pathogenesis of atherosclerosis, epidemiological evidence and the clear genetic association of LDL-C with cardiovascular risk as well as the large statin trials and the reduction of events by a non-statin intervention in the IMPROVE-IT study, the term "hypothesis" appears to be outdated and should be replaced by "LDL-causality".

Reactive oxygen species (ROS) contribute to the pathogenesis of myocardial hypertrophy. NADPH oxidase is a major source of ROS production. The small GTPase Rac1 mediates the activation of NADPH oxidase; however, the mechanism of Rac1 activation is incompletely understood.Transaortic constriction (TAC, C57/Bl6 mice, 360 microm, 21 days) increased the ratio of heart to body weight from [ per thousand] SHAM 4.16+/-0.09 to TAC 7.1+/-0.37, p0.01. Treatment with rosuvastatin prevented pressure-induced cardiac hypertrophy (5.5+/-0.18, p0.05). TAC induced a 4-fold up-regulation of myocardial NADPH oxidase activity as well as Rac1 activity; both effects were absent in statin-treated animals. In cultured rat cardiomyocytes, treatment with angiotensin II (AngII) increased translocation of Rac1 to cell membranes and Rac1 activity. AngII altered neither expression nor tyrosine phosphorylation of GTPase activating protein GAP-p190 and the guanine nucleotide exchange factors Vav and Tiam. Transaortic constriction as well as AngII increased the binding of Rho guanine nucleotide dissociation inhibitor (RhoGDIalpha) to Rac1. The association of RhoGDIalpha with Rac1 was mediated by phosphatidylinositol 3-kinase and depended on geranylgeranylation. Statin treatment inhibited RhoGDIalpha-Rac1 binding both in cultured cardiomyocytes and during myocardial hypertrophy in vivo. Transfection with RhoGDIalpha siRNA constructs potently reduced RhoGDIalpha protein expression, decreased AngII-induced superoxide production and lipid peroxidation, and inhibited AngII-induced leucine incorporation.Myocardial hypertrophy is characterized by activation of Rac1 and NADPH oxidase. The association of the regulatory protein RhoGDIalpha with Rac1 represents a necessary step in the Rac1-dependent release of ROS. Rac1-RhoGDIalpha binding may represent a target for anti-hypertrophic pharmacologic interventions, potentially by statin treatment.

HMG-CoA reductase inhibitors (statins) have been shown to reduce mortality and cardiovascular morbidity in patients with hyperlipidaemia and those with coronary artery disease. However, evidence for statin treatment in patients with chronic heart failure (CHF) remains a subject of debate. Patients with heart failure were generally excluded in the existing trials and a different patient population with a distinct pattern of morbidity and treatment was studied. In addition, no safety data are available for statins in patients with heart failure, where there are potential concerns about coenzyme Q10 depletion and excessive low-density lipoprotein reduction. This review summarises the clinical and preclinical evidence for potential beneficial effects of statins in CHF. In experimental systems, statins have been shown to improve cardiac function through antioxidative and anti-inflammatory action. Statins improve endothelial function, may reduce neurohormonal activation, and stimulate endothelial progenitor cells. Some of these effects occur independently of cholesterol lowering and can be explained by inhibition of isoprenylation of signal transducing proteins of the family of Rho guanosine triphosphatases. Two ongoing controlled randomised trials (CORONA [Controlled Rosuvastatin Multinational Study in Heart Failure] and GISSI-HF [Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico — Heart Failure]) will help us to assess whether the described beneficial effects of statins in heart failure outweigh the potential negative effects and translate into the reduction of clinical endpoints.

Current guidelines from large randomised trials recommend that all patients with diabetes type 2 or coronary artery disease after myocardial infarction should be treated with statin drugs. However, the recent 4D and CORONA trials show no improvement in mortality in elderly patients with ischaemic heart failure and patients with diabetes and end-stage renal disease receiving haemodialysis with the onset of statin treatment. The survival benefit from statin treatment appears to stem primarily from the prevention of progression of coronary artery disease. In clinical conditions where coronary artery disease does not significantly contribute to the cause of death statins seem to be less effective. In patients at risk for organ damage, statin treatment, therefore, has to be started early in the course of the disease. The effect of statin withdrawal in ischaemic heart failure or in patients with advanced renal disease is not known. On the basis of the available evidence, current statin treatment should not be stopped in these patients.

Epidemiologic studies suggest that elevated postprandial triglycerides (ppTG) are associated with future cardiovascular events. Monocyte activation plays an important role in vascular diseases. Omega-3 fatty acids (n3-FA) lower fasting TG levels. The effects of n3-FA on ppTG and the role of ppTG for monocyte activation are insufficiently understood.23 healthy volunteers and 30 non-diabetic patients with documented coronary artery disease were subjected to an oral TG tolerance test (OTTT) consisting of 80 g cream fat or to water as control (H(2)O). Patients were treated with 4 g n3-FA/day or placebo for 3 weeks in a randomized, placebo-controlled, double-blind, crossover study. Relative postprandial TG increase reached its maximum 4 h after fat intake (185.1 ± 10.9% of baseline). n3-FA reduced fasting TG from 137.1 ± 12.9 to 112.2 ± 8.6 mg/dl (p 0.05), and maximum ppTG concentrations from 243.6 ± 24.6 to 205.8 ± 17.1 mg/dl (p 0.05), while relative TG increase (192.8 ± 12.7%) was comparable to placebo. Relative monocytopenia and neutrophilia were detected following fat intake, which was unaffected by n3-FA and also detectable in the H(2)O group. Serum chemotactic cytokine (MCP1 and fractalkine) concentrations and monocyte migration were not affected by fat intake or n3-FA. Monocyte activation markers CD11b and CD14, monocyte subpopulations CD16(+)CD14(high) and CD16(+)CD14(low), sICAM serum levels and markers of oxidative stress remained unchanged by fat intake or n3-FA.The postprandial TG increase does not stimulate monocytes beyond their circadian activation patterns. n3-FA reduce fasting TG and the postprandial TG increase. n3-FA may therefore allow to prospectively study whether selected patients benefit from TG-lowering independent of LDL- and HDL-cholesterol.

Recurrent stroke is a frequent and disabling event. A high heart rate is associated with cardiovascular outcomes. We investigated the effects of the resting heart rate on cardiovascular and neurological outcomes after recurrent stroke in the high-risk population of the PRoFESS study.A total of 20,165 patients after ischaemic stroke (mean age 66.1, SD 8.6 years) assigned to the treatment arms of the PRoFESS trial were pooled divided by quintiles of the baseline heart rate and analysed according to cardiovascular and functional outcomes after stroke: recurrent stroke and major cardiovascular outcomes such as stroke, myocardial infarction, and worsening or new-onset heart failure as well as death from cardiovascular and non-cardiovascular causes. Pre-defined endpoints were disability after a recurrent stroke, assessed with the modified Rankin scale (mRS) and the Barthel index at 3 months, and cognitive function, assessed with the Mini-Mental State Examination (MMSE) score at 4 weeks after randomization and at the penultimate visit. Patients in the two highest quintiles of heart rate (77-82 and82 b.p.m.) were at a higher risk for total death [hazard ratio (HR) 1.42, 95% CI 1.19-1.69 and HR 1.74, 95% CI 1.48-2.06, P0.0001] compared with the lowest quintile. Similar results were observed for vascular death [71-≤76 b.p.m., HR 1.39 (1.11-1.74), P0.0001] and non-vascular death [from82 b.p.m., HR 1.66 (1.29-2.13), P = 0.0016]. Myocardial infarction (P = 0.7084) and recurrent stroke (P = 0.1379) were not significantly associated with the baseline heart rate. Hazard ratios were adjusted to multiple confounders including the baseline blood pressure. In the group of patients with a recurrent stroke, an association of a lower heart rate to better outcomes was measured with the Barthel index across all heart rate groups. In addition, there was a significant association of the baseline heart rate to the occurrence of significant cognitive decline according to an MMSE score ≤24 points at 1 month and at the penultimate visit or a decline of ≥2 points between these two time periods. Better independence score at a low heart rate were observed.The heart rate is a risk indicator for mortality in patients with stroke and, importantly, a low heart rate is associated with a better functional outcome and less cognitive decline after an ischaemic stroke.ClinicalTrials.gov, number NTC00153062.

Background Atherosclerosis is a progressive disease characterised in part by an imbalance of endothelial decline and endothelial repair. Erythropoietin has been connected to vasculoprotective effects such as enhanced nitric oxide production in endothelial cells and mobilisation of endothelial progenitor cells (EPC). Objective To determine the effect of erythropoietin on endothelial function and EPC mobilisation in humans with atherosclerosis. Design A prospective single-blind monocentric study of 20 patients randomly assigned to the test drug or placebo treatment over 4 weeks. Methods 20 Patients with stable coronary artery disease receiving optimal medical treatment with either weekly subcutaneous injections of saline (placebo) or the recombinant erythropoietin darbepoetin (60 μg/injection) over 3 consecutive weeks. At the initial and final visits, flow mediated dilatation (FMD) was determined by ultrasound. The number of EPC was determined as the number of CD34/CD133 positive mononuclear cells in peripheral blood. Results Treatment with darbepoetin resulted in a significantly improved FMD in each patient, whereas no difference was seen in placebo-treated patients. The FMD of darbepoetin-treated patients increased by 7.5±1.64%. Additionally, an increase in peripheral blood EPC of 50±24% was seen. Conclusion Darbepoetin given in addition to optimal medical treatment resulted in a significantly improved endothelial function in patients with coronary artery disease, indicating a promising new atheroprotective treatment option.

Low-density lipoproteins (LDL) are atherogenic and represent a strong cardiovascular risk factor. Therefore, LDL-cholesterol (LDL-C) remains the primary target in lipid lowering therapy. However, since many cardiovascular events occur despite an optimal LDL-C, it is necessary to focus on the remaining cardiovascular risk. Treatment of low high-density lipoprotein-cholesterol (HDL-C) and high triglycerides (TG) are options to achieve cardiovascular risk reduction beyond LDL. HDL mediates reverse cholesterol transport and exerts several other athero-protective effects. Epidemiologic evidence has shown that low HDL-cholesterol (HDL-C) is a strong and independent cardiovascular risk marker. However, since the anti-atherogenic effects of HDL particles rather depend on their functionality rather than on their cholesterol content, an increase in HDL-C concentration does not always have to result in a clinical benefit. Besides established strategies to increase HDL-C, e.g. with fibrates and nicotinic acid, CETP (Cholesteryl ester transfer protein)-inhibition is a promising new therapeutic option. The failure of torcetrapib, the first CETP-inhibitor, seems to be attributed to "off-target" effects. Treatment with the newer CETP-inhibitors dalcetrapib and anacetrapib has been shown to be efficacious and safe - but their usefulness in clinical practice remains to be determined in ongoing clinical endpoint trials. TG concentrations have been shown to correlate with cardiovascular risk. However, interpretation of plasma TG concentrations remains difficult due to considerable intra-individual variability of plasma concentrations. Post-prandial triglyceride concentrations may be better predictors of cardiovascular risk than fasting TG. In patients with hypertriglyceridemia, achievement of the LDL-C goal remains the primary lipid target. The basis of therapy in patients with hypertriglyceridemia are life style modifications. In addition, non-HDL-C should be addressed. For selected patients, treatment with fibrates, nicotinic acid or omega-3 fatty acids are available to lower TG concentrations. In summary, the focus of lipid therapy is the reduction of cardiovascular risk rather than the modification of lipoprotein sub-fractions. Ongoing research points towards a shift of the focus from the HDL-C concentrations to parameters of HDL function and from fasting TG to TG kinetics.

Heart rate influences myocardial oxygen demand, coronary blood flow, and myocardial function. Clinical and experimental studies support an association between elevated resting heart rate and a broad range of maladaptive effects on the function and structure of the cardiovascular system. Heart rate has been shown to be an important predictor of mortality in cardiovascular disorders such as coronary artery disease, myocardial infarction, and chronic heart failure. This review summarizes the specific influence of heart rate on vascular morphology and function as well as on myocardial lesions leading from early impact on vascular homeostasis to myocardial hemodynamics in chronic heart failure. Heart rate can be easily determined during physical examination of the patient and therefore allows a simple hint on prognosis and efficiency of therapy.

This review summarizes the current literature and the open questions regarding the physiology and pathophysiology of the mechanical effects of heart rate on the vessel wall and the associated molecular signaling that may have implications for patient care. Epidemiological evidence shows that resting heart rate is associated with cardiovascular morbidity and mortality in the general population and in patients with cardiovascular disease. As a consequence, increased resting heart rate has emerged as an independent risk factor both in primary prevention and in patients with hypertension, coronary artery disease, and myocardial infarction. Experimental and clinical data suggest that sustained elevation of heart rate—independent of the underlying trigger—contributes to the pathogenesis of vascular disease. In animal studies, accelerated heart rate is associated with cellular signaling events leading to vascular oxidative stress, endothelial dysfunction, and acceleration of atherogenesis. The underlying mechanisms are only partially understood and appear to involve alterations of mechanic properties such as reduction of vascular compliance. Clinical studies reported a positive correlation between increased resting heart rate and circulating markers of inflammation. In patients with coronary heart disease, increased resting heart rate may influence the clinical course of atherosclerotic disease by facilitation of plaque disruption and progression of coronary atherosclerosis. While a benefit of pharmacological or interventional heart rate reduction on different vascular outcomes was observed in experimental studies, prospective clinical data are limited, and prospective evidence determining whether modulation of heart rate can reduce cardiovascular events in different patient populations is needed.

To determine the effect of heart rate reduction with ivabradine on atherosclerotic lesions and erectile dysfunction.Two different treatment regimes with ivabradine were applied in wild-type (C57/B6) and ApoE(-/-)-mice to study effects of ivabradine on erectile function and atherosclerosis in animals with and without present endothelial dysfunction. Preventive effects of ivabradine were evaluated in animals fed a high-cholesterol diet in parallel to treatment with ivabradine (orally via chow, 10 mg/kg per day). The other treatment regime started treatment with a high-cholesterol diet for 4 weeks to induce endothelial dysfunction. Thereafter, treatment with ivabradine (orally via chow, 15 mg/kg per day) was started in ApoE(-/-) mice for 3 months. Vital parameters were measured using the tail-cuff method. Erectile function was assessed by pharmacological stimulation of corpora cavernosa in organ bath chambers. Atherosclerotic plaque formation, oxidative stress, eNOS and collagen content were determined.Treatment with ivabradine significantly reduced heart rate (p0.01), with no effect on blood pressure. Aortic atherosclerotic lesion size decreased with ivabradine in both treatment regimes (p0.05). Endothelium-dependent relaxation of corpora cavernosa significantly decreased in ApoE(-/-)-mice with a restoration by ivabradine in prevention and reversal. Dihydroethidium-stained penile sections (p0.05) and lipid peroxidase assay (p0.05) revealed a reduction in superoxide production in ivabradine-treated animals. Penile eNOS-expression increased and collagen content significantly decreased (p0.01) in ivabradine-treated animals.Ivabradine improves penile endothelial function by reduction of oxidative stress and penile fibrosis. Beneficial effects were achieved in prevention and manifest endothelial dysfunction.

Objective: In epidemiological studies, elevated resting heart rate (HR) is associated with increased cardiovascular morbidity. We therefore characterized the effects of selective heart rate reduction by inhibition of the I (f) -current by ivabradine (IVA) in mice. Methods and Results: Male ApoE −/− mice fed a high-cholesterol diet were treated with IVA (10 mg/kg/d) or vehicle for 6 weeks (n = 10 per group). IVA reduced HR by 13.4% (472 ± 9 vs 545 ± 11 bpm, p < 0.01) but did not alter blood pressure or lipid levels. Endothelium dependent relaxation of aortic rings was significantly improved in IVA fed animals ( p < 0.01). IVA decreased atherosclerotic plaque size in the aortic root by > 40% and in the ascending aorta by > 70%, p < 0.05. HR reduction had no effect on the number of endothelial progenitor cells in the blood and the bone marrow and did not alter aortic eNOS, p-Akt, VCAM-1 or ICAM-1 expression, but decreased MCP-1 mRNA to 26 ± 7% (p < 0.05). IVA reduced vascular NADPH oxidase activity to 48 ± 6% and decreased L-012 chemiluminescence to 24 ± 9% (both p < 0.05). Lipidperoxidation was reduced to 65 ± 8% in the vasculature of the IVA group compared to vehicle treatment (p < 0.05). DHE fluorescence microscopy in aortic sections detected reduction of ROS release to 62 ± 4% in IVA treated mice (p < 0.01). The in vivo effects of IVA were absent at a dose that did not lower HR and were absent in aortic rings treated ex vivo . Protein expression of p-Akt, eNOS and p-eNOS was not altered in cultured endothelial cells (EC) by increasing doses of Iva. Similarly, NADPH oxidase activity in EC was not changed as well as the Ang II induced free radical release in vascular smooth muscle cells (DCF-fluorescence). Conclusions: Selective HR reduction improves endothelial function and reduces atherosclerotic plaque formation in ApoE −/− mice. Those effects are in part mediated by decreased markers of oxidative stress and downregulation of MCP-1. The control experiments show that a direct effect of IVA on vascular cells is unlikely and support the reduction of heart rate as the primary mechanism of action.

Angiotensin receptor blockers enhance endothelial function and are suggested to improve erectile function. The effects and underlying mechanisms of treatment with the angiotensin receptor blocker irbesartan on penile endothelial function in apolipoprotein E (ApoE)(-/-) mice were determined. Wild-type (C57/B6) and ApoE(-/-) mice were fed with a high-fat, cholesterol-rich diet for 7 weeks and treated with irbesartan (50 mg/kg . day) or hydralazine (250 mg/l). Vital parameters were measured with the tail-cuff method. Endothelial (aortic rings) and erectile function (corpora cavernosa) were assessed by pharmacological stimulation in an organ bath chamber. Oxidative stress and angiotensin receptor expression were determined. Blood pressure was significantly decreased in irbesartan- and hydralazine-treated ApoE(-/-) mice (p < 0.05) compared with controls and wild-type mice. Endothelial function of the aorta and corpus cavernosum was significantly impaired in ApoE(-/-) mice (p < 0.05) and could be restored by treatment with irbesartan (p < 0.05). Consistently, nitric oxide production of corpora cavernosa was impaired in ApoE(-/-) mice (p < 0.01), with a restoration in irbesartan- but not hydralazine-treated mice. Dihydroethidium-stained sections and lipid peroxidase assay revealed a reduction of superoxide production in irbesartan (p < 0.05) compared with hydralazine-treated and control ApoE(-/-) mice. In summary, irbesartan improves penile endothelial function in ApoE(-/-) mice by reduction of vascular and cavernosal oxidative stress. This result emphasizes the beneficial effect of inhibition of the renin-angiotensin system even in terms of erectile function.

Background— Elevated heart rate is associated with increased cardiovascular morbidity. We hypothesized that selective heart rate reduction may influence endothelial function and atherogenesis and tested the effects of the I (f) current inhibitor ivabradine in apolipoprotein E–deficient mice. Methods and Results— Male apolipoprotein E–deficient mice fed a high-cholesterol diet were treated with ivabradine (10 mg · kg −1 · d −1 ) or vehicle for 6 weeks (n=10 per group). Ivabradine reduced heart rate by 13.4% (472±9 versus 545±11 bpm; P P 40% and in the ascending aorta by >70% ( P P −1 · d −1 for 6 weeks) reduced blood pressure (−15%) but increased heart rate (37%) and did not improve endothelial function, atherosclerosis, or oxidative stress. Conclusions— Selective heart rate reduction with ivabradine decreases markers of vascular oxidative stress, improves endothelial function, and reduces atherosclerotic plaque formation in apolipoprotein E–deficient mice.

This article summarizes the results of a number of clinical trials in the field of cardiovascular medicine which were presented during the Hotline and Clinical Trial Update Sessions at the annual meeting of the European Society of Cardiology, held in Munich, Germany, from 30th August to 3rd September 2008. The data were presented by leading experts in the field with relevant positions in the trials. It is important to note that unpublished reports should be considered as preliminary data, as the analysis may change in the final publications. The comprehensive summaries have been generated from the oral presentation and the webcasts of the European Society of Cardiology and should provide the readers with the most comprehensive information on diagnostic and therapeutic developments in cardiovascular medicine.

Introduction : Elevated resting heart rate (HR) is associated with increased risk for cardiovascular morbidity and mortality. Erectile dysfunction is associated with endothelial dysfunction and atherosclerosis due to similar risk factors. We hypothesized that HR reduction may influence endothelial- and erectile function and tested the effects of the I f -current inhibitor ivabradine in ApoE−/− mice. Methods and Results: Male ApoE−/− mice fed a high-cholesterol diet were treated with ivabradine (iva) (10 mg/kg/d p.o.) or vehicle (n=10 per group) for 6 weeks. Treatment with ivabradine reduced HR by 13.4% (iva 472±9 bpm vs vehicle 545±11 bpm, p Conclusions : Selective HR reduction improves endothelial as well as erectile function and reduces atherosclerotic plaque formation in ApoE−/− mice. Those functional effects are mediated by decreased oxidative stress and upregulation of endothelial NOS (eNOS). These results identify HR as a risk factor for vascular disease and support the importance of heart rate reduction in vascular prevention.

Klinischen Studien zufolge steigt bei herzinsuffizienten Patienten mit hohem Ruhepuls das kardiale Risiko. Aufgrund strikter Ein- und Ausschlusskriterien sind solche Ergebnisse aber nicht immer ubertragbar. Aktuell zeigte eine grose Registerstudie, dass die Herzfrequenz auch bei einer breiten Patientenpopulation als prognostischer Faktor geeignet ist.

Background —Statins improve endothelial function by upregulating endothelial nitric oxide (NO) production that is mediated by inhibiting the isoprenylation of rho GTPase. Withdrawal of statin treatment could suppress endothelial NO production and may impair vascular function. Methods and Results —To test this hypothesis, mice were treated for 14 days with 10 mg/kg atorvastatin per day; this led to the upregulation of endothelial NO synthase expression and activity by 2.3- and 3-fold, respectively. Withdrawal of statins resulted in a dramatic, 90% decrease of NO production after 2 days. In mouse aortas and cultured endothelial cells, statins upregulated the expression of rho GTPase in the cytosol, but statins blocked isoprenoid-dependent rho membrane translocation and GTP-binding activity. Inhibiting the downstream targets of rho showed that rho expression is controlled by a negative feedback mechanism mediated by the actin cytoskeleton. Measuring rho mRNA half-life and nuclear run-on assays demonstrated that statins or disruption of actin stress fibers increased rho gene transcription but not rho mRNA stability. Therefore, treatment with statins leads to the accumulation of nonisoprenylated rho in the cytosol. Withdrawing statin treatment restored the availability of isoprenoids and resulted in a massive membrane translocation and activation of rho, causing downregulation of endothelial NO production. Conclusions —Withdrawal of statin therapy in normocholesterolemic mice results in a transient increase of rho activity, causing a suppression of endothelial NO production. The underlying molecular mechanism is a negative feedback regulation of rho gene transcription mediated by the actin cytoskeleton.