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Sacubitril/valsartan improves outcomes in chronic heart failure (HF) with reduced ejection fraction (EF). The underlying mechanisms on left ventricular (LV) myocardial function are incompletely understood. In this study, 117 patients with symptomatic HF and LVEF ≤ 40% were enrolled prospectively. Noninvasive pressure-volume analysis was calculated from transthoracic echocardiography with simultaneous arm-cuff blood pressure measurements. Primary outcome parameters were LV end-systolic elastance ( E es ; a measure of LV contractility), effective arterial elastance ( E a ; a measure of afterload), and the ventricular-arterial coupling ratio ( E a / E es ). The mean age was 65 ± 13 yr, 30% were female, and 54.7% had ischemic heart disease. During 6 mo of follow-up, eight patients died, three withdrew their consent, and four were lost to follow-up. About 102 patients were included in pressure-volume analyses. After 6 mo of sacubitril/valsartan treatment, E es increased (0.66 mmHg/mL [IQR 0.45-0.94] vs. 0.78 mmHg/mL [IQR 0.57-1.10], P = 0.001), E a decreased (1.76 mmHg/mL [IQR 1.48-2.13] vs. 1.62 mmHg/mL [IQR 1.36-1.96], P = 0.014), and the E a / E es The study demonstrates that 6-mo treatment with sacubitril/valsartan in patients with heart failure with reduced ejection fraction is associated with increased left ventricular contractility, reduced afterload, and improved ventricular-arterial coupling. Together with reverse remodeling, these changes indicate a leftward shift of the operating left ventricular pressure-volume relationship. These data provide new insights into the understanding of pharmacological mechanisms in the failing heart and may facilitate tailored medical therapy.P < 0.001). LV end-diastolic pressure and LV volumes were reduced, and LVEF increased from 33% to 43% (both P < 0.001). Clinical improvement occurred in NYHA functional class, NT-proBNP level, and 6-min walking distance. Change in LVEF correlated with change in E es ( r = 0.33, P = 0.0008), while change in NT-proBNP was associated with change in LV end-diastolic pressure (LVEDP) ( r = 0.42, P < 0.0001). In conclusion, sacubitril/valsartan is associated with improved ventricular-arterial coupling by enhancing LV contractility and reducing afterload. Beyond LV reverse remodeling, optimized ventricular-arterial interaction may contribute to the favorable outcome of sacubitril/valsartan treatment in HF with reduced EF. NEW & NOTEWORTHY The study demonstrates that 6-mo treatment with sacubitril/valsartan in patients with heart failure with reduced ejection fraction is associated with increased left ventricular contractility, reduced afterload, and improved ventricular-arterial coupling. Together with reverse remodeling, these changes indicate a leftward shift of the operating left ventricular pressure-volume relationship. These data provide new insights into the understanding of pharmacological mechanisms in the failing heart and may facilitate tailored medical therapy.

Heart failure (HF) is associated with poor outcome after stroke, but data from large prospective trials are sparse.We assessed the impact of HF on clinical endpoints in patients hospitalized with acute ischemic stroke or transient ischemic attack (TIA) enrolled in the prospective, multicenter Systematic Monitoring for Detection of Atrial Fibrillation in Patients with Acute Ischemic Stroke (MonDAFIS) trial. HF was defined as left ventricular ejection fraction (LVEF) < 55% or a history of HF on admission. The composite of recurrent stroke, major bleeding, myocardial infarction, and all-cause death, and its components during the subsequent 24 months were assessed. We used estimated hazard ratios in confounder-adjusted models. Overall, 410/2562 (16.0%) stroke patients fulfilled the HF criteria (i.e. 381 [14.9%] with LVEF < 55% and 29 [1.9%] based on medical history). Patients with HF had more often diabetes, coronary and peripheral arterial disease and presented with more severe strokes on admission. HF at baseline correlated with myocardial infarction (HR 2.21; 95% CI 1.02-4.79), and all-cause death (HR 1.67; 95% CI 1.12-2.50), but not with major bleed (HR 1.93; 95% CI 0.73-5.06) or recurrent stroke/TIA (HR 1.08; 95% CI 0.75-1.57). The data were adjusted for age, stroke severity, cardiovascular risk factors, and randomization. Patients with ischemic stroke or TIA and comorbid HF have a higher risk of myocardial infarction and death compared with non-HF patients whereas the risk of recurrent stroke or major hemorrhage was similar. Trial registration number Clinicaltrials.gov NCT02204267., (© 2024. The Author(s).)

Cardiovascular diseases are the most frequent cause of disability and death. Evidence-based pharmacotherapy is the basis for successful treatment of common diseases, such as hypertension, heart failure, coronary artery disease, and atrial fibrillation. The proportion of older people with several diseases (multimorbidity) who need five or more drugs daily (polypharmacy) is steadily increasing. Evidence on the efficacy and safety of drugs in these patients is, however, limited because they are often excluded or underrepresented in clinical trials. In addition, clinical guidelines mostly focus on single diseases and only occasionally deal with the challenges in the pharmacotherapy of older multimorbid patients with polypharmacy. This article describes the options and special features of pharmacotherapy for hypertension, chronic heart failure and dyslipidemia, as well as antithrombotic treatment in (very) old people., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Heart failure (HF) treatment has changed substantially over the last 30 years, leading to significant reductions in mortality and hospital admissions in patients with HF with reduced ejection fraction (HFrEF). Currently, the optimization of guideline-directed chronic HF therapy remains the mainstay to further improve quality of life, mortality, and HF hospitalizations for patients with HFrEF. The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan (S/V) has an important role in the treatment of patients with HFrEF. The PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) randomized controlled trial has established solid evidence for the treatment of HFrEF in various subgroups. Apart from HFrEF, several studies have been conducted using S/V in various indications: patients hospitalized with acute decompensated HF, HF with preserved ejection fraction, acute myocardial infarction with reduced ejection fraction, uncontrolled and resistant hypertension, and chronic kidney disease. Data from the German Institute for Drug Use Evaluation reveal that implementation of S/V has increased steadily over time and, by the end of 2021, an estimated 266 000 patients were treated with S/V in Germany. The estimated cumulative real-world patient exposure is >5.5 million patient-treatment years worldwide. The number of patients treated with S/V largely exceeds the number of patients treated in clinical trials, and the current indication for S/V is larger than the strict inclusion/exclusion criteria of the randomized trials. Especially elderly patients, women, and patients with more and more severe comorbidities are underrepresented in the clinical trials. We therefore aimed to summarize the importance of S/V in HF in terms of efficacy and safety in clinical trials and daily clinical practice., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Surgical and FFP2 masks are recommended to reduce transmission of SARS-CoV-2. The cardiopulmonary effects of facemasks in patients with chronic heart failure are unknown. This prospective, cross-over study quantified the effects of wearing no mask (nm), surgical mask (sm), and FFP2 mask (ffpm) in patients with stable heart failure., Methods: 12 patients with clinically stable chronic heart failure (HF) (age 63.8±12 years, left ventricular ejection fraction (LVEF) 43.8±11%, NTProBNP 573±567 pg/ml) underwent spiroergometry with and without masks in a randomized sequence. Comfort/discomfort was assessed using a standardized questionnaire., Results: Maximum power was reduced with both types of masks (nm: 108.3 W vs. sm: 101.2 W vs. ffpm: 95.6 W, p<0.01). Maximum respiratory oxygen uptake (1499ml/min vs. 1481 ml/min vs. 1300 ml/min, p = 0.95 and <0.01), peak ventilation (62.1 l/min vs. 56.4 l/min vs. 50.3 l/min, p = 0.15 and p<0.05) and O2-pulse (11.6 ml/beat vs. 11.8 ml/beat vs. 10.6 ml/beat, p = 0.87 and p<0.01) were significantly changed with ffpm but not sm. Discomfort was moderately but significantly increased (nm: 1.6 vs. sm: 3.4 vs. ffpm: 4.4, p<0.05)., Conclusion: Both surgical and FFP masks reduce exercise capacity in heart failure patients, while FFP2 masks reduce oxygen uptake and peak ventilation. This reduction in cardiopulmonary performance should be considered in heart failure patients whose daily life activities are often just as challenging as exercise is for healthy adults., Competing Interests: The authors have declared that no competing interests exist.

Patients with heart failure are at a higher risk of cardiovascular events compared with the general population, particularly during domestic or international travel. Patients with heart failure should adhere to specific recommendations during travel to lower their risk of developing heart failure symptoms. In this Review, we aim to provide clinicians with a set of guidelines for patients with heart failure embarking on national or international travel. Considerations when choosing a travel destination include travel distance and time, the season upon arrival, air pollution levels, jet lag and altitude level because all these factors can increase the risk of symptom development in patients with heart failure. In particular, volume depletion is of major concern while travelling given that it can contribute to worsening heart failure symptoms. Pre-travel risk assessment should be performed by a clinician 4-6 weeks before departure, and patients should receive advice on potential travel-related illness and on strategies to prevent volume depletion. Oxygen supplementation might be useful for patients who are very symptomatic. Upon arrival at the destination, potential drug-induced photosensitivity (particularly in tropical destinations) and risks associated with the local cuisine require consideration. Special recommendations are needed for patients with cardiac implantable electronic devices or left ventricular assist devices as well as for those who have undergone major cardiac surgery., (© 2022. Springer Nature Limited.)

Alternative mRNA splicing is a fundamental process to increase the versatility of the genome. In humans, cardiac mRNA splicing is involved in the pathophysiology of heart failure. Mutations in the splicing factor RNA binding motif protein 20 (RBM20) cause severe forms of cardiomyopathy. To identify novel cardiomyopathy-associated splicing factors, RNA-seq and tissue-enrichment analyses were performed, which identified up-regulated expression of Sam68-Like mammalian protein 2 (SLM2) in the left ventricle of dilated cardiomyopathy (DCM) patients. In the human heart, SLM2 binds to important transcripts of sarcomere constituents, such as those encoding myosin light chain 2 (MYL2), troponin I3 (TNNI3), troponin T2 (TNNT2), tropomyosin 1/2 (TPM1/2), and titin (TTN). Mechanistically, SLM2 mediates intron retention, prevents exon exclusion, and thereby mediates alternative splicing of the mRNA regions encoding the variable proline-, glutamate-, valine-, and lysine-rich (PEVK) domain and another part of the I-band region of titin. In summary, SLM2 is a novel cardiac splicing regulator with essential functions for maintaining cardiomyocyte integrity by binding to and processing the mRNAs of essential cardiac constituents such as titin., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: Heart failure (HF) and atrial fibrillation (AF) frequently coexist and are both associated with increased levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP). It is known that AF impairs the diagnostic accuracy of NT-proBNP for HF. The aim of the present study was to compare the diagnostic and predictive accuracy of NT-proBNP for HF and AF in stable outpatients with cardiovascular risk factors., Methods and Results: Data were obtained from the DIAST-CHF trial, a prospective cohort study that recruited individuals with cardiovascular risk factors and followed them up for 12 years. Data were validated in three independent population-based cohorts using the same inclusion/exclusion criteria: LIFE-Adult (n = 2869), SHIP (n = 2013), and SHIP-TREND (n = 2408). Serum levels of NT-proBNP were taken once at baseline. The DIAST-CHF study enrolled 1727 study participants (47.7% female, mean age 66.9 ± 8.1 years). At baseline, patients without AF or HF (n = 1375) had a median NT-proBNP of 94 pg/mL (interquartile range 51;181). In patients with AF (n = 93), NT-proBNP amounted to 667 (215;1130) pg/mL. It was significantly higher than in the first group (P < 0.001) and compared with those with only HF [n = 201; 158 (66;363) pg/mL; P < 0.001]. The highest levels of NT-proBNP [868 (213;1397) pg/mL] were measured in patients with concomitant HF and AF (n = 58; P < 0.001 vs. control and vs. HF, P = 1.0 vs. AF). In patients with AF, NT-proBNP levels did not differ between those with HF and preserved ejection fraction (EF) > 50% [n = 38; 603 (175;1070) pg/mL] and those without HF (P = 1.0). Receiver-operating characteristic curves of NT-proBNP showed a similar area under the curve (AUC) for the detection of AF at baseline (0.84, 95% CI [0.79-0.88]) and for HF with EF < 50% (0.78 [0.72-0.85]; P = 0.18). The AUC for HF with EF > 50% was significantly lower (0.61 [0.56-0.65]) than for AF (P = 0.001). During follow-up, AF was newly diagnosed in 157 (9.1%) and HF in 141 (9.6%) study participants. NT-proBNP was a better predictor of incident AF during the first 2 years (AUC: 0.79 [0.75-0.83]) than of newly diagnosed HF (0.59 [0.55-0.63]; P < 0.001). Data were validated in three independent population-based cohorts (LIFE-Adult, n = 2869; SHIP, n = 2013; and SHIP-TREND, n = 2408)., Conclusions: In stable outpatients, NT-proBNP is a better marker for prevalent and incident AF than for HF. In AF patients, the diagnostic value of NT-proBNP for HF with EF > 50% is very limited., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Patients with heart failure (HF) have poor outcomes, including poor quality of life, and high morbidity and mortality. In addition, they have a high medication burden due to the multiple drug therapies now recommended by guidelines. Previous reviews, including studies in hospital settings, provided evidence that pharmacist care improves outcomes in patients with HF. Because most HF is managed outside of hospitals, we aimed to synthesize the evidence for pharmacist care in outpatients with HF., Methods and Results: We conducted a systematic literature search in PubMed of randomized controlled trials (RCTs) and integrated the evidence on patient outcomes in a meta-analysis. We found 24 RCTs performed in 10 countries, including 8029 patients. The data revealed consistent improvements in medication adherence (independent of the measuring instrument) and knowledge, physical function, and disease and medication management. Sixteen RCTs were included in meta-analyses. Differences in all-cause mortality (odds ratio (OR) = 0.97 [95% CI, 0.84-1.12], Q-statistic, P = 0.49, I 2  = 0%), all-cause hospitalizations (OR = 0.86 [0.73-1.03], Q-statistic, P = 0.01, I 2  = 45.5%), and HF hospitalizations (OR = 0.89 [0.77-1.02], Q-statistic, P = 0.11, I 2  = 0%) were not statistically significant. We also observed an improvement in the standardized mean difference for generic quality of life of 0.75 ([0.49-1.01], P < 0.01), with no indication of heterogeneity (Q-statistic, P = 0.64; I 2  = 0%)., Conclusions: Results indicate that pharmacist care improves medication adherence and knowledge, symptom control, and some measures of quality of life in outpatients with HF. Given the increasing complexity of guideline-directed medical therapy, pharmacists' unique focus on medication management, titration, adherence, and patient teaching should be considered part of the management strategy for these vulnerable patients., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Heart failure (HF) is the most common primary inpatient diagnosis in Germany. We examined temporal trends of HF hospitalization within Germany focusing on regional differences., Methods and Results: We analysed aggregated data of more than 320 million hospitalizations in Germany from 2000 to 2017. Temporal trends of HF-related parameters were analysed, focusing on regional differences between the federal states. The absolute number of HF-related hospitalizations throughout Germany increased continuously and almost doubled (from 239 694 to 464 724 cases, +94%) with the relative increase being higher in East Germany compared with West Germany (119% vs. 88%). These regional differences persisted after age standardization with 609 and 490 cases per 100 000 population, respectively. The length of stay decreased continuously across Germany (from 14.3 to 10.2 days; -29%), while the total number of HF-related hospital days increased by 51% in East Germany and 35% in West Germany. In 2017, HF remained the leading cause of in-hospital death (8.9% of all cases), with a markedly higher rate in East vs. West Germany (65 vs. 43 deaths per 100 000 population)., Conclusions: Heart failure remains the most common cause of hospitalization and in-hospital death throughout Germany. The increase in HF-related morbidity and mortality was much higher in East Germany compared with West Germany during the observation period. A more detailed understanding of these striking disparities 30 years after the German reunification requires further investigations. There is an urgent need for action with regard to stronger control of risk factors and improvement of both chronic HF management and healthcare structures., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Inhibition of sodium-glucose cotransporter 2 (SGLT2) represents an emerging pharmaceutical approach for the treatment of heart failure. The mechanisms by which SGLT2 inhibitors reduce the risk of heart failure are not well understood. The objective of this study was to investigate the association between single nucleotide polymorphisms (SNPs) in the SLC5A2 gene, encoding SGLT2, and heart failure, and to assess potential mediators of this association. Regression and mediation analyses were conducted with individual participant data of the UK Biobank (n = 416,737) and validated in the cardiovascular high-risk cohort of the LUdwigshafen RIsk and Cardiovascular Health study (LURIC; n = 3316). Two intronic SNPs associated with SLC5A2 expression were included in a genetic score, which was associated with lower risk of heart failure in UK Biobank (odds ratio 0.97, 95% confidence interval, 0.95-0.99, P = 0.016). This association was also present in participants without type 2 diabetes or coronary artery disease (CAD). The associations of the genetic score with HbA1c, high-density lipoprotein cholesterol, uric acid, systolic blood pressure, waist circumference, and body composition mediated 35% of the effect of the score on heart failure risk. No associations of the genetic SGLT2 score with atherosclerotic cardiovascular disease outcomes or markers of volume status were observed, which was confirmed in the LURIC study. Variations in the gene encoding SGLT2 were associated with the risk of prevalent or incident heart failure. This association was mediated by several mechanisms and did not depend on the presence of type 2 diabetes or previous CAD events., (© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Aims: White matter lesions (WML) are common structural alterations in the white matter of the brain and their prevalence increases with age. They are associated with cerebral ischaemia and cognitive dysfunction. Patients with heart failure (HF) are at risk for cognitive decline. We hypothesized that the presence and duration of HF are associated with WML., Methods and Results: The LIFE-Adult Study is a population-based study of 10 000 residents of Leipzig, Germany. WML were quantitated in 2490 participants who additionally underwent cerebral MRI using the Fazekas score. Mean age was 64 years, and 46% were female; 2156 (86.6%) subjects had Fazekas score of 0-1, and 334 (13.4%) had Fazekas score of 2-3. Thirty participants had a medical history of HF, 1019 had hypertension, and 51 had a history of stroke. Median left ventricular ejection fraction of the participants with HF was 57% (interquartile ranges 54-62). Age, troponin T, NT-proBNP, body mass index, history of acute myocardial infarction, stroke, HF, and diabetes were positively associated with WML in univariate analysis. On multivariate analysis, age, hypertension, stroke, and HF were independently associated with WML. The odd's ratio for the association of WML (Fazekas 2-3) with HF was 2.8 (95% CI 1.2-6.5; P = 0.019). WML increased with longer duration of HF (P = 0.036 for trend)., Conclusions: In addition to age, hypertension, and stroke, the prevalence and duration of HF are independently associated with WML. This observation sets the stage to investigate the prognostic value of WML in HF and the impact of HF therapies on WML., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Depression is a frequent comorbidity in patients with chronic heart failure (CHF). Telemonitoring has emerged as a novel option in CHF care. However, patients with depression have been excluded in most telemedicine studies. This pre-specified subgroup analysis of the Telemedical Interventional Monitoring in Heart Failure (TIM-HF) trial investigates the effect of telemonitoring on depressive symptoms over a period of 12 months., Methods and Results: The TIM-HF study randomly assigned 710 patients with CHF to either usual care (UC) or a telemedical intervention (TM) using non-invasive devices for daily monitoring electrocardiogram, blood pressure and body weight. Depression was evaluated by the 9-item Patient Health Questionnaire (PHQ-9) with scores ≥10 defining clinically relevant depressive symptoms. Mixed model repeated measures were performed to calculate changes in PHQ-9 score. Quality of life was measured by the Short Form-36. At baseline, 156 patients had a PHQ-9 score ≥10 points (TM: 79, UC: 77) with a mean of 13.2 points indicating moderate depressiveness. Patients randomized to telemedicine showed an improvement of their PHQ-9 scores, whereas UC patients remained constant (P = 0.004). Quality of life parameters were improved in the TM group compared to UC. Adjustment was performed for follow-up, New York Heart Association class, medication, age, current living status, number of hospitalizations within the last 12 months and serum creatinine. In the study population without depression, the PHQ-9 score was similar at baseline and follow-up., Conclusion: Telemedical care improved depressive symptoms and had a positive influence on quality of life in patients with CHF and moderate depression., (© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Endpoints of large-scale trials in chronic heart failure have mostly been defined to evaluate treatments with regard to hospitalizations and mortality. However, patients with heart failure are also affected by very severe reductions in exercise capacity and quality of life. We aimed to evaluate the effects of heart failure treatments on these endpoints using available evidence from randomized trials. Interventions with evidence for improvements in exercise capacity include physical exercise, intravenous iron supplementation in patients with iron deficiency, and - with less certainty - testosterone in highly selected patients. Erythropoiesis-stimulating agents have been reported to improve exercise capacity in anaemic patients with heart failure. Sinus rhythm may have some advantage when compared with atrial fibrillation, particularly in patients undergoing pulmonary vein isolation. Studies assessing treatments for heart failure co-morbidities such as sleep-disordered breathing, diabetes mellitus, chronic kidney disease and depression have reported improvements of exercise capacity and quality of life; however, the available data are limited and not always consistent. The available evidence for positive effects of pharmacologic interventions using angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists on exercise capacity and quality of life is limited. Studies with ivabradine and with sacubitril/valsartan suggest beneficial effects at improving quality of life; however, the evidence base is limited in particular for exercise capacity. The data for heart failure with preserved ejection fraction are even less positive, only sacubitril/valsartan and spironolactone have shown some effectiveness at improving quality of life. In conclusion, the evidence for state-of-the-art heart failure treatments with regard to exercise capacity and quality of life is limited and appears not robust enough to permit recommendations for heart failure. The treatment of co-morbidities may be important for these patient-related outcomes. Additional studies on functional capacity and quality of life in heart failure are required., (© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Bachground: Postprandial hyperlipaemia impairs endothelial function, possibly via oxidative-stress-mediated mechanisms. The aim of this study was to evaluate the acute effects of an oral triglyceride load (OTGL) on peripheral endothelial function in heart failure patients with reduced ejection fraction (HFrEF) compared to healthy controls., Design: Prospective cross-sectional., Methods: We enrolled 47 patients with HFrEF and 20 healthy controls. Peripheral endothelial function was assessed with EndoPAT2000 technology using a reactive hyperaemia index (RHI) and pulse wave amplitude (PWA) at baseline (after 8-h overnight fasting) as well as 1, 2, 3 and 4-h post-OTGL consumption (250-ml cream drink). Pulse wave amplitude index (PWAI) was calculated as a ratio of PWA at each time point to the baseline PWA., Results: RHI at baseline was lower in HFrEF patients compared to controls (1.7 ± 0.3 and 2.3 ± 0.6, respectively; P = 0.001). The OTGL accounted for a physiologic increase in PWA in healthy controls (p = 0.01), but this change was not observed in HFrEF patients. After 4 h, vasodilator response was significantly increased in healthy controls but not patients with HFrEF (2.3 ± 1.3 vs. 1.3 ± 0.8 respectively, P < 0.05)., Conclusions: The main finding of this study was the impaired postprandial dynamic changes in peripheral endothelial function in patients with HFrEF compared to healthy controls. A high-fat load that caused acute hypertriglyceridaemia significantly increased resting blood flow and peak flow at reactive hyperaemia in healthy subjects. By contrast, patients with HFrEF exhibited impaired dynamic changes in peripheral endothelial function after oral triglyceride load., Competing Interests: Declaration of Competing Interest On behalf of all authors, the corresponding author states that there is no conflict of interest., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aims: Atrial fibrillation (AF) is a frequent comorbidity in patients with heart failure (HF). HF patients with AF are characterized by high morbidity and increased risk of hospitalizations. We assessed the effects of remote patient management (RPM) in HF patients with AF compared with usual care (UC) in the TIM-HF2 trial., Methods and Results: For this post-hoc analysis, AF status at randomization was assessed in 1537 patients with HF. The primary outcome was the percentage of days lost due to unplanned cardiovascular hospital admissions or death of any cause. Around 966 patients had sinus rhythm (SR) and 571 had AF. The analysis showed a significant interaction between heart rhythm and all-cause mortality (P for interaction = 0.001). AF patients had more days lost due to unplanned cardiovascular hospitalization than SR patients (7.53%, CI 6.01-9.05 vs. 4.90%, CI 3.98-5.82, ratio 1.54, P = 0.004) and higher all-cause mortality (11.9%, CI 9.4-14.9 vs. 8.5%, CI 6.8-10.4, HR 0.66, CI 0.47-0.94, P = 0.029). Patients with AF randomized to RPM had significantly less days lost due to unplanned cardiovascular hospital admissions or all-cause death (5.64%, CI 3.81-7.48) than patients with AF randomized to UC (9.37%, CI 6.98-11.76, ratio 0.60, P = 0.015). No difference was seen in SR patients (UC: 5.25%, CI 3.93-6.58, RPM: 4.55%, CI 3.27-5.83, ratio 0.87, P = 0.452). All-cause mortality in AF patients was reduced with 9.2% (CI 6.1-13.2) in the RPM group compared with 14.5% (CI 10.7-18.1) in the UC group (HR 0.60, CI 0.36-1.00, P = 0.050)., Conclusions: For patients with atrial fibrillation at study entry, RPM was associated with increased days alive out of hospital. Our results identify HF patients with atrial fibrillation as a promising target population for RPM., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

In contrast to the wealth of proven therapies for heart failure with reduced ejection fraction (HFrEF), therapeutic efforts in the past have failed to improve outcomes in heart failure with preserved ejection fraction (HFpEF). Moreover, to this day, diagnosis of HFpEF remains controversial. However, there is growing appreciation that HFpEF represents a heterogeneous syndrome with various phenotypes and comorbidities which are hardly to differentiate solely by LVEF and might benefit from individually tailored approaches. These hypotheses are supported by the recently presented PARAGON-HF trial. Although treatment with LCZ696 did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among HFpEF patients, subanalyses suggest beneficial effects in female patients and those with an LVEF between 45 and 57%. In the future, prospective randomized trials should focus on dedicated, well-defined subgroups based on various information such as clinical characteristics, biomarker levels, and imaging modalities. These could clarify the role of LCZ696 in selected individuals. Furthermore, sodium-glucose cotransporter-2 inhibitors have just proven efficient in HFrEF patients and are currently also studied in large prospective clinical trials enrolling HFpEF patients. In addition, several novel disease-modifying drugs that pursue different strategies such as targeting cardiac inflammation and fibrosis have delivered preliminary optimistic results and are subject of further research. Moreover, innovative device therapies may enhance management of HFpEF, but need prospective adequately powered clinical trials to confirm safety and efficacy regarding clinical outcomes. This review highlights the past, present, and future therapeutic approaches in HFpEF.

Aims: Medication non-adherence is frequent and is associated with high morbidity and mortality in patients with chronic heart failure (CHF). We investigated whether an interdisciplinary intervention improves adherence in elderly CHF patients., Methods and Results: The study population (mean age 74 years, 62% male, mean left ventricular ejection fraction 47%, 52% in New York Heart Association class III) consisted of 110 patients randomized into the pharmacy care and 127 into the usual care group. The median follow-up was 2.0 years (interquartile range 1.2-2.7). The pharmacy care group received a medication review followed by regular dose dispensing and counselling. Control patients received usual care. The primary endpoint was medication adherence as proportion of days covered (PDC) within 365 days for three classes of heart failure medications (beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and mineralocorticoid receptor antagonists). The main secondary outcome was the proportion of adherent patients (PDC ≥ 80%). The primary safety endpoint was days lost due to unplanned cardiovascular hospitalizations (blindly adjudicated) or death. Pharmacy care compared with usual care resulted in an absolute increase in mean adherence to three heart failure medications for 365 days [adjusted difference 5.7%, 95% confidence interval (CI) 1.6-9.8, P = 0.007]. The proportion of patients classified as adherent increased (odds ratio 2.9, 95% CI 1.4-5.9, P = 0.005). Pharmacy care improved quality of life after 2 years (adjusted difference in Minnesota Living with Heart Failure Questionnaire scores -7.8 points (-14.5 to -1.1; P = 0.02), compared to usual care. Pharmacy care did not affect the safety endpoints of hospitalizations or deaths., Conclusion: Pharmacy care safely improved adherence to heart failure medications and quality of life., (© 2019 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Medication adherence correlates with morbidity and mortality in patients with chronic heart failure (CHF), but is difficult to assess. We conducted a retrospective methodological cohort study in 3,808 CHF patients, calculating adherence as proportion of days covered (PDC) utilizing claims data from 2010 to 2015. We aimed to compare different parameters' influence on the PDC of elderly CHF patients exemplifying a complex chronic disease. Investigated parameters were the assumed prescribed daily dose (PDD), stockpiling, and periods of hospital stay. Thereby, we investigated a new approach using the PDD assigned to different percentiles. The different dose assumptions had the biggest influence on the PDC, with variations from 41.9% to 83.7%. Stockpiling and hospital stays increased the values slightly. These results queries that a reliable PDC can be calculated with an assumed PDD. Hence, results based on an assumed PDD have to be interpreted carefully and should be presented with sensitivity analyses to show the PDC's possible range., (© 2019 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Fibrosis is a hallmark of maladaptive cardiac remodelling. Here we report that genome-wide quantitative trait locus (QTL) analyses in recombinant inbred mouse lines of C57BL/6 J and DBA2/J strains identified Raf Kinase Inhibitor Protein (RKIP) as genetic marker of fibrosis progression. C57BL/6 N-RKIP -/- mice demonstrated diminished fibrosis induced by transverse aortic constriction (TAC) or CCl 4 (carbon tetrachloride) treatment compared with wild-type controls. TAC-induced expression of collagen Iα2 mRNA, Ki67 + fibroblasts and marker of oxidative stress 8-hydroxyguanosine (8-dOHG) + fibroblasts as well as the number of fibrocytes in the peripheral blood and bone marrow were markedly reduced in C57BL/6 N-RKIP -/- mice. RKIP-deficient cardiac fibroblasts demonstrated decreased migration and fibronectin production. This was accompanied by a two-fold increase of the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2), the main transcriptional activator of antioxidative proteins, and reduced expression of its inactivators. To test the importance of oxidative stress for this signaling, C57BL/6 J mice were studied. C57BL/6 J, but not the C57BL/6 N-strain, is protected from TAC-induced oxidative stress due to mutation of the nicotinamide nucleotide transhydrogenase gene (Nnt). After TAC surgery, the hearts of Nnt-deficient C57BL/6 J-RKIP -/- mice revealed diminished oxidative stress, increased left ventricular (LV) fibrosis and collagen Iα2 as well as enhanced basal nuclear expression of Nrf2. In human LV myocardium from both non-failing and failing hearts, RKIP-protein correlated negatively with the nuclear accumulation of Nrf2. In summary, under conditions of Nnt-dependent enhanced myocardial oxidative stress induced by TAC, RKIP plays a maladaptive role for fibrotic myocardial remodeling by suppressing the Nrf2-related beneficial effects.

We report the rationale and design of a community PHARMacy-based prospective randomized controlled interdisciplinary study for ambulatory patients with Chronic Heart Failure (PHARM-CHF) and results of its pilot study. The pilot study randomized 50 patients to a pharmacy-based intervention or usual care for 12 months. It demonstrated the feasibility of the design and showed reduced systolic blood pressure in the intervention group as indicator for improved medication adherence. The main study will randomize patients ≥60 years on stable pharmacotherapy including at least one diuretic and a history of heart failure hospitalization within 12 months. The intervention group will receive a medication review at baseline followed by regular dose dispensing of the medication, counselling regarding medication use and symptoms of heart failure. The control patients are unknown to the pharmacy and receive usual care. The primary efficacy endpoint is medication adherence, pre-specified as a significant difference of the proportion of days covered between the intervention and control group within 365 days following randomization using pharmacy claims data for three CHF medications (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists). The primary composite safety endpoint is days lost due to blindly adjudicated unplanned cardiovascular hospitalizations or death. Overall, 248 patients shall be randomized. The minimum follow-up is 12 months with an expected mean of 24 months. Based on the feasibility demonstrated in the pilot study, the randomized PHARM-CHF trial will test whether an interdisciplinary pharmacy-based intervention can safely improve medication adherence and will estimate the potential impact on clinical endpoints. ClinicalTrials.gov Identifier: NCT01692119., (© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.)

Secondary mitral regurgitation (MR) results from left ventricular dilatation and dysfunction. Quantification of secondary MR is challenging because of the underlying myocardial disease. Clinical and echocardiographic evaluation requires a multi-parametric approach. Severe secondary MR occurs in up to one-fourth of patients with heart failure with reduced ejection fraction, which is associated with a mortality rate of 40% to 50% in 3 years. Percutaneous edge-to-edge mitral valve repair (MitraClip) has emerged as an alternative to surgical valve repair to improve symptoms, functional capacity, heart failure hospitalizations, and cardiac haemodynamics. Further new transcatheter strategies addressing MR are evolving. The Carillion, Cardioband, and Mitralign devices were designed to reduce the annulus dilatation, which is a frequent and important determinant of secondary MR. Several transcatheter mitral valve replacement systems (Tendyne, CardiAQ-Edwards, Neovasc, Tiara, Intrepid, Caisson, HighLife, MValve System, and NCSI NaviGate Mitral) are emerging because valve replacement might be more durable compared with valve repair. In small studies, these interventional therapies demonstrated feasibility and efficiency to reduce MR and to improve heart failure symptoms. However, neither transcatheter nor surgical mitral valve repair or replacement has been proven to impact on the prognosis of heart failure patients with severe MR, which remains high with a mortality rate of 14-20% at 1 year. To date, the primary indication for treatment of secondary severe MR is the amelioration of symptoms, reinforcing the value of a Heart Team discussion. Randomized studies to investigate the treatment effect and long-term outcome for any transcatheter or surgical mitral valve intervention compared with optimized medical treatment are urgently needed and underway., (© 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Heart failure (HF) is a complex clinical syndrome with multiple interactions between the failing myocardium and cerebral (dys-)functions. Bi-directional feedback interactions between the heart and the brain are inherent in the pathophysiology of HF: (i) the impaired cardiac function affects cerebral structure and functional capacity, and (ii) neuronal signals impact on the cardiovascular continuum. These interactions contribute to the symptomatic presentation of HF patients and affect many co-morbidities of HF. Moreover, neuro-cardiac feedback signals significantly promote aggravation and further progression of HF and are causal in the poor prognosis of HF. The diversity and complexity of heart and brain interactions make it difficult to develop a comprehensive overview. In this paper a systematic approach is proposed to develop a comprehensive atlas of related conditions, signals and disease mechanisms of the interactions between the heart and the brain in HF. The proposed taxonomy is based on pathophysiological principles. Impaired perfusion of the brain may represent one major category, with acute (cardio-embolic) or chronic (haemodynamic failure) low perfusion being sub-categories with mostly different consequences (i.e. ischaemic stroke or cognitive impairment, respectively). Further categories include impairment of higher cortical function (mood, cognition), of brain stem function (sympathetic over-activation, neuro-cardiac reflexes). Treatment-related interactions could be categorized as medical, interventional and device-related interactions. Also interactions due to specific diseases are categorized. A methodical approach to categorize the interdependency of heart and brain may help to integrate individual research areas into an overall picture., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

To determine and address medication non-adherence is important and may improve patient outcomes. Our aim was to perform a systematic review on the operationalization of adherence measures in patients with heart failure using claims data. We searched the MEDLINE, EMBASE, and Cochrane databases. A quality check of the full-text articles was performed using the Quality in Prognosis Studies tool. We included 28 studies. Eleven studies used the medication possession ratio, 15 the proportion of days covered, and six studies used own methods to calculate medication adherence. Almost all studies used an observation period of 1 year. Twenty-one studies considered angiotensin converting enzyme inhibitors or angiotensin receptor antagonists, 17 beta-blockers, 11 diuretics, eight mineralocorticoid receptor antagonists, six digitalis-glycosides, and six statins. Eight studies looked at single substance classes; 18 studies analyzed more than one drug class. Different assumptions for the dosage were used. In seven studies, switching within therapeutic classes was allowed. Three studies allowed stockpiling, nine studies censored hospital stays, and four studies censored death. Seventeen studies dichotomized the results, applying the cutoff ≥ 0.8 to define a patient as adherent. Eight studies analyzed adherence as a continuous value. The reporting quality of the methodology applied varied widely between studies. A gold standard is currently not available for the quantification of medication adherence in patients with chronic heart failure via claims data. To assess the methodology, the following parameters should be described: method of measurements, observation period, substances, dosing, switches, stockpiling, truncations, statistical analysis, and cutoff for adherence.

About 50% of all patients suffering from heart failure (HF) exhibit a reduced ejection fraction (EF ≤ 40%), termed HFrEF. The others may be classified into HF with midrange EF (HFmrEF 40-50%) or preserved ejection fraction (HFpEF, EF ≥ 50%). Presentation and pathophysiology of HFpEF is heterogeneous and its management remains a challenge since evidence of therapeutic benefits on outcome is scarce. Up to now, there are no therapies improving survival in patients with HFpEF. Thus, the treatment targets symptom relief, quality of life and reduction of cardiac decompensations by controlling fluid retention and managing risk factors and comorbidities. As such, renin-angiotensin-aldosterone inhibitors, diuretics, calcium channel blockers (CBB) and beta-blockers, diet and exercise recommendations are still important in HFpEF, although these interventions are not proven to reduce mortality in large randomized controlled trials. Recently, numerous new treatment targets have been identified, which are further investigated in studies using, e.g. soluble guanylate cyclase stimulators, inorganic nitrates, the angiotensin receptor neprilysin inhibitor LCZ 696, and SGLT2 inhibitors. In addition, several devices such as the CardioMEMS, interatrial septal devices (IASD), cardiac contractility modulation (CCM), renal denervation, and baroreflex activation therapy (BAT) were investigated in different forms of HFpEF populations and some of them have the potency to offer new hopes for patients suffering from HFpEF. On the basic research field side, lot of new disease-modifying strategies are under development including anti-inflammatory drugs, mitochondrial-targeted antioxidants, new anti-fibrotic and microRNA-guided interventions are under investigation and showed already promising results. This review addresses available data of current best clinical practice and management approaches based on expert experiences and summarizes novel approaches towards HFpEF.

A standardized medication plan (MP) was recently enacted into German law (§ 31a SGB V). The purpose of our study was to assess if patients with chronic diseases requiring polymedication understand the standardized MP and can transfer the given information into practice. 100 patients who took at least five medicines regularly were prospectively included in a cross-sectional study: 50 patients with the primary diagnosis chronic heart failure (CHF), and 50 with diabetes mellitus type 2 (DMT2). We performed a structured test-scenario studying the handling of a provided MP then evaluated the execution of the information on the MP by filling pill boxes and requested patients' opinion. An established weighted scoring system, the "Evaluation Tool to test the handling of the Medication Plan" (ET-MP) was applied to quantitate the ability of the patients to handle the MP. In addition, signs of depression, cognitive function and self-care behavior in chronic heart failure were characterized using the PHQ-9, Mini-Cog, and G9-EHFScB-9 questionnaires, respectively. The understanding of the MP was poor and irrespective of the underlying primary diagnosis. Only 32% of all patients were able to handle the MP without difficulties (ET-MP score >90%), the median ET-MP score was 83 [(IQR) 50-98]. Comprehension of the MP was better in patients aged <70 years compared to ≥70 years (p<0.01). Patients ≥10 years of education achieved higher ET-MP results than patients with <10 years of education (p<0.01). Patients with signs of cognitive impairment exhibited significantly lower ET-MP scores than patients without cognitive impairment (p<0.001). There were no significant correlations of the ET-MP score with number of daily medications, living situation, sex, the Charlson Comorbidity Index, the PHQ-9 score, and use of a dosing aid or possession of a medication list.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

B-type natriuretic peptides are markers of myocardial wall stress. BNP or NT-proBNP are used for the differential diagnosis of acute dyspnoe where normal serum concentrations make a cardiac cause unlikely. New data show their importance for risk prediction in different stages of heart failure and in primary prevention. Natriuretic peptide guided therapy improves titration of heart failure medications. Compared to BNP, NT-proBNP is better suited during therapy with the new angiotensin-rezeptor-neprilysin-inhibitor Sacubitril/Valsartan. This review article summarizes current data on the importance of B-type natriuretic peptides for the interface of ambulatory and hospital care and presents recommendations for their practical use in patient care., (© Georg Thieme Verlag KG Stuttgart · New York.)

Mitochondrial reactive oxygen species (ROS) play a central role in most aging-related diseases. ROS are produced at the respiratory chain that demands NADH for electron transport and are eliminated by enzymes that require NADPH. The nicotinamide nucleotide transhydrogenase (Nnt) is considered a key antioxidative enzyme based on its ability to regenerate NADPH from NADH. Here, we show that pathological metabolic demand reverses the direction of the Nnt, consuming NADPH to support NADH and ATP production, but at the cost of NADPH-linked antioxidative capacity. In heart, reverse-mode Nnt is the dominant source for ROS during pressure overload. Due to a mutation of the Nnt gene, the inbred mouse strain C57BL/6J is protected from oxidative stress, heart failure, and death, making its use in cardiovascular research problematic. Targeting Nnt-mediated ROS with the tetrapeptide SS-31 rescued mortality in pressure overload-induced heart failure and could therefore have therapeutic potential in patients with this syndrome., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Chronic heart failure (CHF) is prevalent among the elderly and is characterized by high mortality and hospitalization rates. Non-adherence to medications is frequent and related to poor clinical outcomes. It is often assumed that older age is related to poorer medication adherence compared with younger age. We analyzed the existing evidence of age as a determinant of medication adherence in patients with CHF., Methods: A systematic search of the bibliographic database MEDLINE and all Cochrane databases was performed. Studies were included if they examined medication adherence in adult patients with CHF, evaluated factors contributing to medication adherence, and analyzed the relationship between age and medication adherence. Articles classified as studies with poor quality were excluded., Results: A total of 1565 titles were found, and ultimately, 17 studies, which provide data for a total of 162,727 patients, were analyzed. Seven studies showed a statistically significant relationship between age and medication adherence: six articles demonstrated that increased age is correlated with higher medication adherence, and one study showed that patients in the age range of 57 to 64 years are affected by non-adherence to angiotensin-converting enzyme inhibitors. Ten studies found no significant relationship., Conclusions: The results suggest that older age alone is not related to poorer medication adherence compared with younger patients with CHF. More attention should be paid to younger newly-diagnosed patients with CHF. Future studies are required to explore medication adherence in CHF in different, standardized, and specific age groups and should be sufficiently powered to assess clinical endpoints., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Evidence-based pharmacotherapy improves morbidity and mortality in patients with chronic heart failure (CHF). Medication adherence management is important for the effectiveness and safety of treatment. This study investigated drugs stored at home by elderly CHF patients., Methods and Results: One hundred and one patients with stable CHF age ≥65 years were visited at home where a standardized interview and a thorough assessment of medication were performed. Mean age of the patients was 77.7 ± 6.1 years, 53 % male, mean NYHA functional class of 2.8 ± 0.7 and a Minnesota-Living-with-Heart-Failure score of 59.4 ± 28.6 points indicating reduced quality of life. The mean number of different drug packs per patient was 13.1 ± 5.5, corresponding to a mean indexed value per patient of 403 ± 48. Cardiovascular drugs accounted for 32 % of the packs. On average, 2.4 ± 3.2 packs contained medication that was not taken by the patient (18 % of the medication, mean indexed value 61 ± 8). Fifty-six percent of the unused drugs were prescribed by general practitioners, 23 % in the hospital, and 7 % by medical specialists and 14 % were over-the-counter drugs. Sixty-three packages (5 %) of the drugs at home were expired (mean indexed value per patient 12 ± 3)., Conclusion: On average, elderly patients with CHF have to manage 13 different drug packs per day at home of which a significant portion is not taken as prescribed. New strategies are needed to support medicines management at home.

Despite of markedly improved options for treatment, chronic heart failure is associated with recurrent worsening of symptoms. Poor medication adherence has adverse effects on frequency and progression of congestive heart failure. There are three relevant areas of problems that could be aggravated by each other:There is the problem of changes in pharmacokinetics in worsening heart failure. Proportional to the severity of heart failure, there is an existing intestinal edema and changes of intestinal bacterial colonization that may affect a drug's absorption and, hence, its efficacy.Depression and impaired cognitive function is quite common in patients with chronic heart failure. Depression both predicts hospitalization and mortality rate as well as poor medication adherence in CHF. Compared to stable CHF patients, cognitive function deteriorates significantly while decompensation leading to impaired medication adherence.Shown by recent studies, there is a higher risk for poor medication adherence after a cardiovascular event.Poor medication adherence is associated with an increased rate of cardiovascular events not only in heart failure, but also in all cardiovascular diseases. Hence, there is a need for specific and long term interventions to improve medication adherence at an early stage., (© Georg Thieme Verlag KG Stuttgart · New York.)

Chronic heart failure (CHF) is one of the leading causes of hospitalization, morbidity, and mortality worldwide. This review summarizes current knowledge with regard to CHF as a risk factor for ischemic stroke. CHF is associated with an increased risk of thrombus formation and is accompanied by a 2- to 3-fold increased risk of stroke. Moreover, stroke in CHF patients is associated with poor outcome and higher mortality. Available evidence for additional "vascular" stroke risk factors in heart failure patients is inconsistent and is mostly derived from cohort studies or retrospective analyses. Current guidelines recommend anticoagulation for CHF patients with concomitant atrial fibrillation but not for those in sinus rhythm. Prospective studies are needed to test whether early detection and optimal treatment of CHF reduces the burden of stroke-associated neurologic and neuropsychological sequelae.

Chronic heart failure (CHF) is one of the leading causes of hospitalization, morbidity and mortality. Moreover, there is a high rate of neurological as well as neuropsychological comorbidities, namely ischemic stroke, structural brain alterations, cognitive impairment, sleep apnea and possible side-effects of HF medication such as delirium or (intracerebral) hemorrhage. The higher stroke risk in patients with HF increases further with age, concomitant arterial hypertension or atrial fibrillation (AF). In women the stroke risk increases with reduced ejection fraction (EF). In general stroke in HF patients is associated with a poor outcome and higher mortality, which is increased more than 2-fold. Furthermore, approximately 25-80% of all patients with CHF experience cognitive impairments such as decreased attention and concentration, memory loss, diminished psychomotor reaction time and decreased executive functions. Cognitive impairment in patients with HF has been linked to losses in gray matter, (silent) ischemic strokes, decreased cerebral perfusion and higher mortality. Moreover, sleep apnea occurs in more than half of all patients with CHF and reduced EF. However, prospective studies are needed to test whether early detection and optimal treatment of HF reduces the burden of neurological and neuropsychological sequelae.

Stroke contributes significantly to morbidity, mortality, and disability worldwide. Despite the successes accomplished in the acute treatment and rehabilitation of stroke, the global burden of this disease can only be tackled with co-ordinated approaches for primary prevention. Stroke is a heterogeneous disease and the contribution of individual risk factors to its occurrence estimated by population attributable risk differs from coronary heart disease. Here, we review evidence to demonstrate the prominent role of elevated blood pressure (BP) and heart disease on risk of stroke, while the influence of lipids on stroke is less clear; we also demonstrate that stroke is an important complication of heart failure. Current approaches to primary preventive action emphasize the need to target the absolute risk of cardiovascular diseases rather than individual risk factors. Lifestyle interventions serve as a basis for primary prevention of cardiovascular diseases. It is estimated that 70% of strokes are potentially preventable by lifestyle modification but prospective evidence is needed to support these hypotheses derived from epidemiological studies. Different strategies for drug interventions in primary prevention are discussed, including the polypill strategy. Additional measures are needed for the primary prevention of stroke which focus on BP, chronic heart failure, and possibly lipids.

Inflammation and pro-hypertrophic signaling are important for development and progression of myocardial hypertrophy (LVH) and chronic heart failure (CHF). Here we investigated the relevance of integrin-linked kinase (ILK) for chemokine receptor CXCR4- and angiotensin II type 1-triggered signaling and its regulation and role in cardiac remodeling. Using ELISA, real-time-PCR, and Western blotting, the present study demonstrates that SDF-1 and its receptor CXCR4 are up-regulated in plasma and left ventricles, respectively, in mouse models of cardiac hypertrophy (transaortic constriction, transgenic cardiac-specific overexpression of rac1) and in human CHF in association with increased cardiac ILK-expression. In isolated cardiomyocytes, ILK is activated by CXCR4-ligation and necessary for SDF-1-triggered activation of rac1, NAD(P)H oxidase, and release of reactive oxygen species. Importantly, the pro-hypertrophic peptide angiotensin II induces ILK-activation dependent on rac1 in cardiomyocytes, where ILK is necessary for angiotensin II-mediated stimulation of hypertrophy genes and protein synthesis. We conclude that in both SDF-1- and angiotensin II-triggered signaling, ILK is a central mediator of rac1-induced oxidative stress and myocardial hypertrophy., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

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.

Atrial fibrillation (AF) and chronic heart failure (CHF) can be caused by each other, and therefore constitute a vicious circle. The prevalence of both conditions is about 1% in industrialized countries and increases with age. Although mortality is increased in heart failure, the additional prognostic relevance of AF in these patients is less clear. AF in patients with CHF can worsen heart failure symptoms, cause complications (eg, stroke), and is difficult to treat. Thus, prevention of AF entirely is an important goal. This review summarizes recent data concerning prognostic relevance, treatment, and means of primary and secondary prevention of AF in patients with CHF.

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.

The effect of statins to reduce mortality and morbidity in primary and secondary prevention as well as in acute coronary syndrome is well established. Recent data show that pleiotropic effects might also have direct effects on the myocardial cell. However, in chronic heart failure the outcome is inversely related to LDL-plasma concentrations and other pleiotropic effects might impair mitochondrial function. Since there are no safety data on the use of statins in chronic heart failure, a controlled randomized and placebo-controlled trial is urgently needed.

Objective: HMG CoA reductase inhibitors (statins) may exert a wide array of cholesterol independent effects including antihypertrophic effects on the heart. Their role in the treatment of heart failure has not been studied., Methods and Results: 15 patients with heart failure NYHA II-III based on non-ischemic dilated cardiomyopathy were randomized in a double-blind study to 0.4 mg cerivastatin or placebo for an average treatment period of 20 weeks. Quality of life and exercise capacity increased significantly in the statin treatment but not in the placebo group (Minnesota Living with Heart Failure Questionnaire, 6 min walking test). Concomitantly, there was a trend towards increased left ventricular ejection fraction (radionuclear ventriculography) and improved endothelial function (forearm blood flow). Statins decreased plasma concentrations of troponine T, high sensitive C-reactive protein (hsCRP), plasminogen activator inhibitor-1 (PAI-1) and tumor necrosis factor alpha (TNFalpha)., Conclusions: Statins induce beneficial effects in patients with non-ischemic cardiomyopathy leading to improvement of quality of life and exercise capacity disclosing a promising novel treatment strategy for patients with heart failure.