Cardiac MRI-based right-to-left ventricular blood pool T2 relaxation times ratio correlates with exercise capacity in patients with chronic heart failure.

BACKGROUND: MRI T2 mapping has been proven to be sensitive to the level of blood oxygenation. We hypothesized that impaired exercise capacity in chronic heart failure is associated with a greater difference between right (RV) to left ventricular (LV) blood pool T2 relaxation times due to a higher level of peripheral blood desaturation, compared to patients with preserved exercise capacity and to healthy controls. METHODS: Patients with chronic heart failure (n = 70) who had undergone both cardiac MRI (CMR) and a 6-min walk test (6MWT) were retrospectively identified. Propensity score matched healthy individuals (n = 35) served as control group. CMR analyses included cine acquisitions and T2 mapping to obtain blood pool T2 relaxation times of the RV and LV. Following common practice, age- and gender-adjusted nominal distances and respective percentiles were calculated for the 6MWT. The relationship between the RV/LV T2 blood pool ratio and the results from 6MWT were evaluated by Spearman's correlation coefficients and regression analyses. Inter-group differences were assessed by independent t-tests and univariate analysis of variance. RESULTS: The RV/LV T2 ratio moderately correlated with the percentiles of nominal distances in the 6MWT (r = 0.66) while ejection fraction, end-diastolic and end-systolic volumes showed no correlation (r = 0.09, 0.07 and - 0.01, respectively). In addition, there were significant differences in the RV/LV T2 ratio between patients with and without significant post-exercise dyspnea (p = 0.001). Regression analyses showed that RV/LV T2 ratio was an independent predictor of the distance walked and the presence of post-exercise dyspnea (p < 0.001). CONCLUSION: The proposed RV/LV T2 ratio, obtained by two simple measurements on a routinely acquired four-chamber T2 map, was superior to established parameters of cardiac function to predict exercise capacity and the presence of post-exercise dyspnea in patients with chronic heart failure.

FoCUS cardiac ultrasound training for undergraduates based on current national guidelines: a prospective, controlled, single-center study on transferability.

INTRODUCTION: In emergency and critical-care medicine, focused cardiac ultrasound (FoCUS) is indispensable for assessing a patient's cardiac status. The aim of this study was to establish and validate a peer-to-peer-supported ultrasound course for learning FoCUS-specific skills during undergraduate studies at a German university. METHODS: A 1-day, 12 teaching units training course was developed for students in the clinical section of medical college, with content based on the current national guidelines. A total of 217 students participated in the study (97 in the course group and 120 in the control group). The course and the participants' subjective assessment of improved skills were evaluated using a questionnaire (7-point Likert scale; 7 = complete agreement and 1 = no agreement at all). Objective learning gains were assessed by tests before and after the course. These consisted of a test of figural intelligence (eight items) and a test of technical knowledge (13 items). RESULTS: The course participants experienced significant improvement (P < 0.001) from before to after the course, with a large effect size of η2part = 0.26. In addition, the course group had significantly better results (P < 0.001) than the control group in the post-test, with a medium to large effect size of η2part = 0.14. No significant differences (P = 0.27) were detected in the test section on figural intelligence. The evaluations showed that the participants had a high degree of satisfaction with the course approach, teaching materials, and tutors. There was also a positive increase in their subjective assessment of their own skills, including areas such as technical knowledge, ultrasound anatomy, and performance of the examination. CONCLUSION: The results of both the objective learning assessment and the subjective evaluations suggest that a FoCUS course originally intended for qualified physicians is equally suitable for students. With the development and provision of modern digital teaching media, even more students will be able to benefit from this approach in the future.

Quality of oral anticoagulation with phenprocoumon in regular medical care and its potential for improvement in a telemedicine-based coagulation service--results from the prospective, multi-center, observational cohort study thrombEVAL.

BACKGROUND: The majority of studies on quality of oral anticoagulation (OAC) therapy with vitamin K-antagonists are performed with short-acting warfarin. Data on long-acting phenprocoumon, which is frequently used in Europe for OAC therapy and is considered to enable more stable therapy adjustment, are scarce. In this study, we aimed to assess quality of OAC therapy with phenprocoumon in regular medical care and to evaluate its potential for optimization in a telemedicine-based coagulation service. METHODS: In the prospective observational cohort study program thrombEVAL we investigated 2,011 patients from regular medical care in a multi-center cohort study and 760 patients from a telemedicine-based coagulation service in a single-center cohort study. Data were obtained from self-reported data, computer-assisted personal interviews, and laboratory measurements according to standard operating procedures with detailed quality control. Time in therapeutic range (TTR) was calculated by linear interpolation method to assess quality of OAC therapy. Study monitoring was carried out by an independent institution. RESULTS: Overall, 15,377 treatment years and 48,955 international normalized ratio (INR) measurements were analyzed. Quality of anticoagulation, as measured by median TTR, was 66.3% (interquartile range (IQR) 47.8/81.9) in regular medical care and 75.5% (IQR 64.2/84.4) in the coagulation service (P <0.001). Stable anticoagulation control within therapeutic range was achieved in 63.8% of patients in regular medical care with TTR at 72.1% (IQR 58.3/84.7) as compared to 96.4% of patients in the coagulation service with TTR at 76.2% [(IQR 65.6/84.7); P = 0.001)]. Prospective follow-up of coagulation service patients with pretreatment in regular medical care showed an improvement of the TTR from 66.2% (IQR 49.0/83.6) to 74.5% (IQR 62.9/84.2; P <0.0001) in the coagulation service. Treatment in the coagulation service contributed to an optimization of the profile of time outside therapeutic range, a 2.2-fold increase of stabile INR adjustment and a significant decrease in TTR variability by 36% (P <0.001). CONCLUSIONS: Quality of anticoagulation with phenprocoumon was comparably high in this real-world sample of regular medical care. Treatment in a telemedicine-based coagulation service substantially improved quality of OAC therapy with regard to TTR level, frequency of stable anticoagulation control, and TTR variability. TRIAL REGISTRATION: ClinicalTrials.gov, unique identifier NCT01809015, March 8, 2013.

A nationwide trend analysis on the usage of endomyocardial biopsy.

BACKGROUND: Endomyocardial biopsy (EMB) is a safe procedure performed in diagnostic work-up of cardiac disease. HYPOTHESIS: Data regarding temporal trends of total numbers, characteristics, in-hospital outcomes, and complications of patients undergoing EMB are sparse. METHODS: The nationwide German inpatient sample (2005-2019) was used for this analysis. Patient cases of EBM during the 5-year cycles from 2005 to 2009, 2010 to 2014, and 2015 to 2019 were compared, and temporal trends regarding total numbers and presumable major and minor EMB-associated complications were investigated. RESULTS: Overall, 67 745 EMB were performed in Germany 2005-2019. Total number of EMB increased from 3083 in 2005 to 5646 in 2019 (ß 0.40 [95% confidence interval [CI] 0.37-0.43], p < .001). Among these EMB, 19 083 (28.2%) were performed during the period 2005-2009, 22 867 (33.7%) 2010-2014, and 25 795 (38.1%) between 2015 and 2019. The proportion of patients aged ≥70 years was highest 2015-2019 (2005-2009: 9.3%; 2010-2014: 13.8%; 2015-2019: 16.1%, p < .001) and the most aggravated comorbidity profile (Charlson Comorbidity Index 2.25 ± 1.93; 2.67 ± 2.14; 3.01 ± 2.29, p < .001) was also detected 2015-2019. Major complications occurred less often in the period 2015-2019 compared to 2005-2009 (odds ratio [OR] 0.921 [95% CI 0.893-0.950], p < .001), whereas minor complications were more frequently observed between 2015 and 2019 (OR 1.067 [95% CI 1.042-1.093], p < .001). While a decrease in major complications was detected irrespective of age, an increase in minor complications was identified only in patients between 30-59 years. CONCLUSIONS: Annual numbers of EMB increased significantly in Germany 2005-2019. Patients who underwent EMB in recent years were older and showed an aggravated comorbidity profile accompanied by fewer major complications, underscoring safety of the procedure.

Development and Phenotype of Heart Failure in Long-Term Survivors of Childhood Cancer: The CVSS Study.

Background The CVSS (Cardiac and Vascular Late Sequelae in Long-Term Survivors of Childhood Cancer) study aimed to investigate the prevalence of different stages of heart failure (HF) in childhood cancer survivors (CCSs) compared with the general population. Methods and Results A total of 1002 CCSs (age range, 23-48 years) diagnosed with neoplasia before an age of 15 years underwent a comprehensive cardiovascular screening. An age- and sex-matched sample from the population-based GHS (Gutenberg Health Study) served as a comparison group. Although prevalence of HF was significantly higher in CCSs, prevalence of different HF stages varied strongly by specific tumor history. Compared with the population, the prevalence ratio was 2.6 (95% CI, 2.4-2.8) for HF stage A and 4.6 (95% CI, 4.1-5.1) for the composite of HF stage B to D in an age- and sex-adjusted Poisson regression model. Multivariable linear regression, adjusting for tumor entities, age, sex, and cardiovascular risk factors, revealed a lower left ventricular ejection fraction in patients with history of bone tumors (ß, -4.30 [95% CI, -5.70 to -2.80]), soft tissue sarcoma (ß, -1.60 [95% CI, -2.90 to -0.30]), and renal tumors (ß, -1.60 [95% CI, -2.80 to -0.29]) compared with the population. The same model for the diastolic marker, ratio of the peak early diastolic filling velocity/lateral mitral annular early diastolic velocity, showed an association only with cardiovascular risk factors but not with tumor entities. Conclusions The prevalence of HF stage A to D was significantly higher among long-term CCSs compared with the population and varied strongly by tumor entity. Systolic dysfunction was primarily associated with tumor entities, whereas diastolic dysfunction was associated with a higher burden of cardiovascular risk factors in CCSs.

Successful treatment of doxorubicin-induced cardiomyopathy with low-dose sacubitril/valsartan: a case report.

Background: Cancer therapy-related cardiac dysfunction (CTRCD) is a challenging and life-threatening complication of many chemotherapeutic regimens. CTRCD prevention, diagnosis, and therapy require both careful interdisciplinary assessment and management. For patients with CTRCD, current guidelines of the European Society of Cardiology (ESC) recommend an angiotensin-converting-enzyme inhibitor in combination with a beta-blocker. Recent studies indicate a beneficial effect of sacubitril/valsartan in this patient population. Case summary: A 68-year-old female patient with a pleural epithelioid angiosarcoma developed heart failure with reduced ejection fraction and elevated serum biomarkers following doxorubicin treatment. After implementation of a recommended cardioprotective medical therapy including torasemide, ramipril, carvedilol, and spironolactone, the patient suffered two cardiac decompensations within 4 weeks after initiation of a paclitaxel regimen and pleural radiation therapy due to pain exacerbation. Despite a continuous application of the cardioprotective medical treatment regimen, no improvement of left-ventricular ejection fraction (LVEF) was detected in a 4-month follow up. Interestingly, after omitting ramipril and implementing low-dose sacubitril/valsartan (26/24 mg), we observed a decrease in serum biomarkers within 3 months as well as a significant improvement of LVEF within 6 months. After nearly 10 months of disease stabilization under paclitaxel, the patient suffered progressive cancer disease and deceased 1 week later after the initiation of a therapeutic attempt with pazopanib. Discussion: This case report highlights the importance of interdisciplinary care in cancer patients as well as the promising role of (low-dose) sacubitril/valsartan in patients with CTRCD even in the setting of delayed initiation.

Impact of cardiac amyloidosis on outcomes of patients hospitalized with heart failure.

BACKGROUND: Amyloidosis is a multi-systemic disease potentially leading to failure of affected organs. We aimed to investigate prevalence and prognostic implications of cardiac amyloidosis of any etiology on outcomes of hospitalized patients with heart failure (HF) in Germany. METHODS: We analyzed data of the German nationwide inpatient sample (2005-2018) of patients hospitalized for HF (including myocarditis with HF and heart transplantation with HF). HF patients with amyloidosis (defined as cardiac amyloidosis [CA]) were compared with those HF patients without amyloidosis and impact of CA on outcomes was assessed. RESULTS: During this fourteen-year observational period 5,478,835 hospitalizations for HF were analyzed. Amyloidosis was coded in 5,407 HF patients (0.1%). CA prevalence was 1.87 hospitalizations per 100,000 German population. CA patients were younger (75.0[IQR 67.0-80.0]vs.79.0[72.0-85.0]years, p < 0.001), predominantly male (68.9%) and had a higher prevalence of cancer (14.8% vs. 3.6%, p < 0.001). Adverse in-hospital events including necessity of transfusions of blood constituents (7.1% vs. 5.4%, p < 0.001) and cardio-pulmonary resuscitation (CPR, 2.7% vs. 1.4%; p < 0.001) were more frequent in CA. CA was independently associated with acute kidney failure (OR 1.40 [95%CI 1.28-1.52], p < 0.001), CPR (OR 1.58 [95%CI 1.34-1.86], p < 0.001), intracerebral bleeding (OR 3.13 [95%CI 1.68-5.83], p < 0.001) and in-hospital mortality between the 5 and 8th decade of life, but in-hospital mortality was strongly influenced by cancer. CONCLUSIONS: CA was identified as an independent risk factor for complications and in-hospital mortality in HF patients, whereby it has to be mentioned that amyloidosis subtypes could not differentiated in the present study. Physicians should be aware of this issue concerning treatments and monitoring of CA-patients.

Atherosclerosis and Its Impact on the Outcomes of Patients with Deep Venous Thrombosis.

Introduction: Atherosclerosis and pulmonary embolism (PE) affect cardiovascular mortality substantially. We aimed to investigate the impact of atherosclerosis on the outcomes of patients with deep venous thrombosis (DVT) and to identify the differences in DVT patients with and without PE. Methods: Patients with DVT with and without symptomatic atherosclerosis (defined as coronary artery disease, myocardial infarction and/or peripheral artery disease) as well as with and without PE under oral anticoagulation were enrolled during January 2011−April 2013 and compared. The impact of symptomatic atherosclerosis on several outcomes was analyzed. Results: Overall, 509 DVT patients (70.0 [56.0−77.0] years, 51.9% females) were included in this study. Among them, 179 (36.3%) had symptomatic atherosclerosis and 204 (40.1%) a concomitant PE. DVT patients with symptomatic atherosclerosis were older (74.0 [IQR 65.0−80.0] vs. 63.0 [48.0−75.0] years, p < 0.0001), more often male (56.4% vs. 43.9%, p = 0.0087) and had a higher prevalence of classical CVRF and a higher Charlson comorbidity index (7.00 [5.00−8.00] vs. 4.00 [2.00−6.00], p < 0.001). Symptomatic atherosclerosis was associated with increased mortality (HR 1.98 [95%CI 1.12−3.49], p = 0.018) and hospitalizations (HR 1.64 [95%CI 1.21−2.21], p = 0.0012) and primary long-term outcome (HR 1.99 [95%CI 1.31−3.04], p = 0.0013) during the 2 years follow-up-period in DVT patients. DVT patients without PE had diabetes mellitus (28.2% vs. 16.3%, p < 0.01) and symptomatic atherosclerosis (42.9% vs. 26.4%, p < 0.001) more often compared to DVT patients with PE, and symptomatic atherosclerosis was associated with isolated DVT (without PE) (OR 2.01 [95%CI 1.28−3.16], p < 0.01). Conclusions: Atherosclerosis was associated with isolated DVT (without PE) and increased mortality in DVT patients under oral anticoagulation. The profile of CVRF and comorbidities differed between DVT patients with and without a concomitant PE. In the case of DVT or PE, patients should be screened for concomitant atherosclerotic disease. Clinical Trial Registration: at clinicaltrials with Unique identifier NCT01809015.

Telomere Shortening in Hypertensive Heart Disease Depends on Oxidative DNA Damage and Predicts Impaired Recovery of Cardiac Function in Heart Failure.

BACKGROUND: Heart failure (HF) coincides with cardiomyocyte telomere shortening. Arterial hypertension is the most prominent risk factor for HF. Both HF and arterial hypertension are associated with dysregulation of the neurohormonal axis. How neurohormonal activation is linked to telomere shortening in the pathogenesis of HF is incompletely understood. METHODS: Cardiomyocyte telomere length was assessed in a mouse model of hypertensive HF induced by excess neurohormonal activation (AngII [angiotensin II] infusion, high salt diet, and uninephrectomy), in AngII-stimulated cardiomyocytes and in endomyocardial biopsies from patients with HF. Superoxide production, expression of NOX2 (NADPH oxidase 2) and PRDX1 (peroxiredoxin 1) and HDAC6 (histone deacetylase 6) activity were assessed. RESULTS: Telomere shortening occurred in vitro and in vivo, correlating with both left ventricular (LV) dilatation and LV systolic function impairment. Telomere shortening coincided with increased superoxide production, increased NOX2 expression, increased HDAC6 activity, loss of the telomere-specific antioxidant PRDX1, and increased oxidative DNA-damage. NOX2 knockout prevented PRDX1 depletion, DNA-damage and telomere shortening confirming this enzyme as a critical source of reactive oxygen species. Cotreatment with the NOX inhibitor apocynin ameliorated hypertensive HF and telomere shortening. Similarly, treatment with the HDAC6 inhibitor tubastatin A, which increases PRDX1 bioavailability, prevented telomere shortening in adult cardiomyocytes. To explore the clinical relevance of our findings, we examined endomyocardial biopsies from an all-comer population of patients with HF with reduced ejection fraction. Here, cardiomyocyte telomere length predicted the recovery of cardiac function. CONCLUSIONS: Cardiomyocyte telomere shortening and oxidative damage in heart failure with reduced ejection fraction induced by excess neurohormonal activation depends on NOX2-derived superoxide and may help to stratify HF therapy.

Temporal trends and predictors of inhospital death in patients hospitalised for heart failure in Germany.

AIMS: We investigated trends in incidence, case fatality rate, patient characteristics and adverse inhospital events of patients hospitalised for heart failure in Germany. METHODS AND RESULTS: The German nationwide inpatient sample (2005-2016) was used for this analysis. Patients hospitalised due to heart failure were selected for analysis. Temporal trends in the incidence of hospitalisations, case fatality rate and treatments were analysed and predictors of inhospital death were identified. The analysis comprised a total number of 4,539,140 hospitalisations (52.0% women, 81.0% aged ≥70 years) due to heart failure. Although hospitalisations increased from 381 (2005) to 539 per 100,000 population (2016) (ß estimate 0.06, 95% confidence interval (CI) 0.06 to 0.07, P < 0.001) in parallel with median age and prevalence of comorbidities, the inhospital case fatality rate decreased from 11.1% to 8.1% (ß estimate -0.36, 95% CI -0.37 to -0.35, P < 0.001) and the rate of major adverse cardiovascular and cerebrovascular events (ß estimate -0.24, 95% CI -0.25 to -0.23, P < 0.001) decreased from 12.7% to 10.3%. Age 70 years and older (odds ratio (OR) 2.60, 95% CI 2.57 to 2.63, P < 0.001) and cancer (OR 1.93, 95% CI 1.91 to 1.96, P < 0.001) were independent predictors of inhospital death. CONCLUSION: Hospitalisations for heart failure increased in Germany from 2005 to 2016, whereas the major adverse cardiovascular and cerebrovascular event rate and inhospital case fatality rate decreased during this period despite higher patient age and increasing prevalence of comorbidities.

Rationale, design and baseline characteristics of the MyoVasc study: A prospective cohort study investigating development and progression of heart failure.

BACKGROUND: Heart failure (HF) is a poly-aetiological syndrome with large heterogeneity regarding clinical presentation, pathophysiology, clinical outcome and response to therapy. The MyoVasc study (NCT04064450) is an epidemiological cohort study investigating the development and progression of HF. METHODS: The primary objective of the study is (a) to improve the understanding of the pathomechanisms of HF across the full spectrum of clinical presentation, (b) to investigate the current clinical classifications of HF, and (c) to identify and characterize homogeneous subgroups regarding disease development using a systems-oriented approach. Worsening of HF, that is, the composite of transition from asymptomatic to symptomatic HF, hospitalization due to HF, or cardiac death, was defined as the primary endpoint of the study. During a six-year follow-up period, all study participants receive a highly standardized, biannual five-hour examination in a dedicated study centre, including detailed cardiovascular phenotyping and biobanking of various biomaterials. Annual follow-up examinations are conducted by computer-assisted telephone interviews recording comprehensively the participants´ health status, including subsequent validation and adjudication of adverse events. RESULTS: In total, 3289 study participants (age range: 35 to 84 years; female sex: 36.8%) including the full range of HF stages were enrolled from 2013 to 2018. Approximately half of the subjects (n=1741) presented at baseline with symptomatic HF (i.e. HF stage C/D). Among these, HF with preserved ejection fraction was the most frequent phenotype. CONCLUSIONS: By providing a large-scale, multi-dimensional biodatabase with sequential, comprehensive medical-technical (sub)clinical phenotyping and multi-omics characterization (i.e. genome, transcriptome, proteome, lipidome, metabolome and exposome), the MyoVasc study will help to advance our knowledge about the heterogeneous HF syndrome by a systems-oriented biomedicine approach. TRIAL REGISTRATION: ClinicalTrials.gov; NCT04064450.

Association of Global Longitudinal Strain With Clinical Status and Mortality in Patients With Chronic Heart Failure.

Importance: Global longitudinal strain (GLS) is an emerging echocardiographic biomarker of cardiac function in heart failure (HF). Evidence from large-scale studies comprehensively investigating GLS for its association with clinical phenotypes and mortality in asymptomatic and symptomatic chronic HF is limited. Objective: To assess the factors associated with GLS and its prognostic value in patients with chronic HF. Design, Setting, and Participants: The observational, prospective MyoVasc cohort study enrolled 3289 individuals with asymptomatic to symptomatic HF between January 17, 2013, and April 27, 2018. The median follow-up was 3.2 years (interquartile range, 2.0-4.0 years). Participants with stages A to D HF according to American Heart Association (AHA) criteria were examined at a dedicated study center. Echocardiography was performed with GLS measurement by independent reviewers. Data were analyzed from September 2, 2019, to January 15, 2020. Main Outcomes and Measures: All-cause and cardiac mortality were recorded by structured follow-up and validated via death certificates. Results: In the study sample, data on GLS were available on 2440 individuals, of whom 2186 (mean [SD] age, 65.0 [10.5] years; 1418 [64.9%] men) were classified as having AHA HF stages A to D. Mean (SD) GLS worsened across AHA stages from stage A (n = 434; -19.44 [3.15%]) to stage B (n = 629; -18.01 [3.46%]) to stages C/D (n = 1123; -15.52 [4.64%]). Age (ß = -0.27; 95% CI, -0.47 to -0.067; per decade, P = .009), female sex (ß = -1.2; 95% CI, -1.6 to -0.77; per decade, P < .001), obesity (ß = 0.64; 95% CI, 0.25-1.0; P = .001), atrial fibrillation (ß = 1.2; 95% CI, 0.69-1.6; P < .001), myocardial infarction (ß = 1.5; 95% CI, 1.00-2.1; P < .001), and estimated glomerular filtration rate (ß = -0.53; 95% CI, -0.73 to -0.32; per SD, P < .001) were independently associated with GLS in multivariable regression analysis. Global longitudinal strain was associated with the severity of HF as reflected by N-terminal prohormone B-type natriuretic protein (NT-proBNP) levels after additionally adjusting for cardiac structure and function (P < .001). During follow-up, GLS was associated with all-cause mortality (hazard ratio [HR] per SD, 1.55; 95% CI, 1.19-2.01; P < .001) and cardiac death (HR per SD, 2.32; 95% CI, 1.57-3.42; P < .001) independent of image quality, observer variability, clinical profile, HF medications, NYHA class, and cardiac structure and function. After further adjustment for the NT-proBNP level, GLS remained associated with cardiac death (HR per SD, 1.60; 95% CI, 1.07-2.41; P = .02) but not all-cause mortality (HR per SD, 1.26; 95% CI, 0.95-1.66; P = .11). Conclusions and Relevance: In patients with chronic HF, GLS was associated with clinical and cardiac status, reflected neurohormonal activation, and was associated with cardiac mortality independent of clinical and cardiac status. These findings suggest that GLS may serve as a useful tool to improve risk stratification in patients with HF.

The relevance of depressive symptoms for the outcome of patients receiving vitamin K antagonists: results from the thrombEVAL cohort study.

AIMS: Although depressive symptoms are highly prevalent in patients receiving oral anticoagulation (OAC), the relevance of depression for the outcome of anticoagulated individuals is unknown. METHODS AND RESULTS: We analysed data from the multicentre cohort study thrombEVAL (NCT01809015) investigating the efficacy of OAC with vitamin K antagonists. There was an independent study monitoring, and an independent review panel assessed the endpoints. Out of n = 1558 participants, information about depressive symptoms, as measured by the two-item screener of the patient health questionnaire (PHQ-2), was available in n = 1405 individuals. The mean follow-up period was 28.04 months, with a standard deviation of 11.52 months. In multivariable Cox regression analysis, baseline PHQ-2 sum score was a strong and robust predictor of clinically relevant bleeding [hazard ratio (HR) 1.13, 95% confidence interval 1.03-1.24; P = 0.011] and all-cause mortality (HR 1.18, 1.08-1.28; P = 0.001) independent of age, sex, high school graduation, partnership, clinical profile, intake of serotonin reuptake inhibitors, and quality of OAC therapy. Individuals with clinically significant depressive symptoms (PHQ-2 ≥ 3) had a 57% increased risk for clinically relevant bleeding (fully adjusted HR 1.57, 1.08-2.28) and 54% greater risk for death (fully adjusted HR 1.54, 1.09-2.17). There was no association of depressive symptoms with thromboembolic events. For hospitalization, individuals with depressive symptoms (PHQ-2 ≥ 3) did not experience an elevated risk in the fully adjusted model (HR 1.08, 0.86-1.35; P = 0.52). CONCLUSION: Assessment of depression by the PHQ-2 provided independent long-term prognostic information beyond common biomedical risk factors. These findings highlight the need for targeting depressive symptoms in the management of patients receiving OAC therapy.

The impact of platelet indices on clinical outcome in heart failure: results from the MyoVasc study.

AIMS: Platelet indices have been associated with traditional cardiovascular risk factors, cardiovascular diseases and all-cause mortality. This study aimed to investigate the role of platelet count, mean platelet volume (MPV) and platelet-to-leukocyte ratio, including platelet-to-monocyte and platelet-to-lymphocyte ratio with cardiac function, heart failure (HF) phenotypes and clinical outcome, worsening of HF. METHODS AND RESULTS: Univariate and multivariable linear and Cox regression analyses were used to investigate the associations between platelet indices, cardiac function and worsening of HF in 3250 subjects enrolled in the MyoVasc study. Higher MPV, lower platelet count, lower platelet-to-leukocyte and platelet-to-monocyte ratios have been associated with reduced left ventricular ejection fraction (beta estimate [ß]MPV [fL]  = -0.05 [-0.09; -0.02], ßplatelet count (× 10/L)9  = 3.4 [1.2; 5.6], ßplatelet-to-leukocyte ratio  = 1.4 [1.1; 1.8], ßplatelet-to-monocyte ratio  = 28 [20; 36]) and increased E/E' ratio (ß MPV [fL]  = 0.04 [0.003; 0.07], ßplatelet count (× 10/L)9  = -3.1 [-5.3; -0.92], ßplatelet-to-leukocyte ratio  = -0.83 [-1.2; -0.46], ßplatelet-to-monocyte ratio  = -20 [-28; -12]), independent of age and sex. Cox regression demonstrated an increased risk for worsening of HF in subjects with MPV > 75th percentile (hazard ratio [HR] = 1.47 [1.16; 1.87]), platelet count < 25th percentile (HR = 1.36 [1.07; 1.74]), platelet-to-leukocyte < 25th percentile (HR = 1.53 [1.20; 1.95]), platelet-to-monocyte < 25th percentile (HR = 1.38 [1.08; 1.77]) and platelet-to-lymphocyte > 75th percentile (HR = 1.50 [1.17; 1.93]) ratios, independent of potential confounders. MPV > 75th percentile and platelet count < 25th percentile were strongly related to outcome in HFpEF vs. HFrEF (P for difference = 0.040). Platelet-to-leukocyte ratios were associated with worse outcome in both HF phenotypes, without a significant difference between HFpEF and HFrEF. CONCLUSIONS: Platelet indices are linked with worse cardiac function and adverse clinical outcome, independent of subjects' underlying cardiovascular profile. This study emphasizes their important value to provide additional information on pathophysiology and risk stratification in HF syndrome.

Promotion of Arterial Stiffness by Childhood Cancer and Its Characteristics in Adult Long-Term Survivors.

Background Vascular alterations induced by antineoplastic treatment might be considered as a possible underlying mechanism of increased cardiovascular sequelae in childhood cancer survivors (CCSs). We aimed to evaluate arterial stiffness among long-term CCSs and to compare the data against a population-based sample. Methods and Results Arterial stiffness was assessed by digital photoplethysmography (stiffness index; m/s) among 1002 participants of the CVSS (Cardiac and Vascular Late Sequelae in Long-Term Survivors of Childhood Cancer) study, diagnosed with neoplasia (1980-1990) before an age of 15 years. A population-based sample from the GHS (Gutenberg Health Study) (n=5252) was investigated for comparison. All subjects underwent a comprehensive, standardized clinical examination in the same study center. CCSs had higher stiffness index (ß=0.66 m/s; 95% CI, 0.51-0.80 m/s) in multivariable linear regression analysis after adjustment for cardiovascular risk factors compared with the population sample of comparable age range. Stiffer vessels were found among CCSs also in absence of arterial hypertension (ß=0.66; 95% CI, 0.50-0.81) or history of chemotherapy/radiotherapy (ß=0.56; 95% CI, 0.16-0.96) in fully adjusted models. Moreover, stiffness index differed by tumor entity, with highest values in bone and renal tumors. Almost 5.2-fold higher prevalence of stiffness index values exceeding age-specific, population-based reference limits was observed among CCSs compared with GHS participants. Conclusions This is the first study demonstrating increased arterial stiffness among long-term CCSs. The data suggest that vascular compliance might differ in survivors of childhood cancer from the established development concept for arterial stiffness in the population; cancer growth and antineoplastic treatment might be relevant determinants of the pathobiological features. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02181049.

Cost saving analysis of specialized, eHealth-based management of patients receiving oral anticoagulation therapy: Results from the thrombEVAL study.

To evaluate the cost-saving of a specialized, eHealth-based management service (CS) in comparison to regular medical care (RMC) for the management of patients receiving oral anticoagulation (OAC) therapy. Costs of hospitalization were derived via diagnosis-related groups which comprise diagnoses (ICD-10) and operation and procedure classification system (OPS), which resulted in OAC-related (i.e. bleeding/ thromboembolic events) and non-OAC-related costs for both cohorts. Cost for anticoagulation management comprised INR-testing, personnel, and technical support. In total, 705 patients were managed by CS and 1490 patients received RMC. The number of hospital stays was significantly lower in the CS cohort compared to RMC (CS: 23.4/100 py; RMC: 68.7/100 py); with the most pronounced difference in OAC-related admissions (CS: 2.8/100 py; RMC: 13.3/100 py). Total costs for anticoagulation management amounted to 101 EUR/py in RMC and 311 EUR/py in CS, whereas hospitalization costs were 3261 [IQR 2857-3689] EUR/py in RMC and 683 [504-874] EUR/py in CS. This resulted in an overall cost saving 2368 EUR/py favoring the CS. The lower frequency of adverse events in anticoagulated patients managed by the telemedicine-based CS compared to RMC translated into a substantial cost-saving, despite higher costs for the specialized management of patients.Trial registration: ClinicalTrials.gov, unique identifier NCT01809015, March 8, 2013.

Sex-specific differences drive temporal trends and outcomes of patients hospitalized for heart failure in Germany.

BACKGROUND: Despite remarkable improvements in treatment of cardiovascular disease, heart failure (HF) is still characterized by high mortality rate. Sex-specific differences in HF have been described, but underlying reasons are widely unexplored. METHODS: The nationwide German inpatient sample (2005-2016) was used for this sex-specific analyses. Temporal trends on hospitalizations, mortality, and treatments were analysed and independent predictors of adverse outcomes identified. RESULTS: The analysis comprises 4,538,977 hospitalizations due to HF (52.0%women) in Germany (2005-2016). Although women were older (median 82(IQR75-87) vs.76(69-82),P < 0.001), coronary artery disease (CAD, 50.3% vs. 30.7%,P < 0.001) was more prevalent in men, who were more often treated with percutaneous intervention (PCI;3.4% vs. 1.4%,P < 0.001) and implantable cardioverter-defibrillator (2.2% vs. 0.5%,P < 0.001). In-hospital mortality was significantly lower in men than in women (8.9% vs.10.2%,P = 0.001) and was reduced in patients who received PCI or implantation of an implantable cardioverter-defibrillator. While total numbers of hospitalizations between 2005 and 2016 increased in both men (ß-estimate 7185.71 (95%CI 6502.23 to 7869.18),P < 0.001) and women (ß-estimate 5297.60 (95%CI 4557.37 to 6037.83),P < 0.001) as well as almost all comorbid co-conditions, in-hospital mortality rate decreased more distinctly in women (ß-estimate -0.41 (95%CI -0.42 to -0.39),P < 0.001) compared to men (ß-estimate -0.29 (95%CI -0.30 to -0.27),P < 0.001). CONCLUSIONS: Interventional treatments of HF were associated with improved outcomes and equally beneficial for both sexes. However, they were more often used in male HF patients, in which CAD is significantly more frequent than in female HF patients. This may explain the higher case fatality rate of HF in females.

Safety of transradial and transfemoral left ventricular compared with transfemoral right ventricular endomyocardial biopsy.

AIMS: With the present study, we sought to determine the safety of three different endomyocardial biopsy (EMB) access routes in 514 patients admitted for diagnostic workup of heart failure of unknown aetiology. METHODS AND RESULTS: In this retrospective monocentric cohort study, we analysed 514 consecutive patients with heart failure without evidence of significant coronary artery disease or valvular disease undergoing EMB between November 2013 and December 2018, stratified in three access route groups: transradial arterial left ventricular (LV-)EMB (323 patients), transfemoral LV-EMB (138 patients), and transfemoral right ventricular (RV-)EMB (53 patients). Patients undergoing selective transradial LV-EMB were older compared with patients undergoing selective transfemoral LV-EMB or RV-EMB [transradial LV-EMB: 56.0 (45.0/64.0) vs. transfemoral LV-EMB: 53 (42.5/64.5), P = 0.455; transradial LV-EMB: 56 (45.0/64.0) vs. RV-EMB: 53 (42.5/64), P = 0.695] and presented more often in New York Heart Association-functional class III and IV. A total of eight major complications including permanent atrioventricular block requiring pacemaker implantation, pericardial tamponade necessitating pericardiocentesis, stroke and transient cerebral ischaemic attack as well as severe valvular damage, vascular access site complications, and ventricular fibrillation were documented with no significant differences between the groups (8/514, 1.5%). Minor complications such as transient chest pain, non-sustained electrocardiogram abnormalities, and transient atrioventricular block were rare and equally distributed between groups. CONCLUSIONS: Transradial LV-EMB is a safe procedure for experienced radial operators and non-inferior compared with transfemoral LV-EMB and RV-EMB. An accurate peri-procedural and post-procedural monitoring and follow-up care should be recommended for all patients undergoing this procedure in order to identify potential complications.

Specialized Management of Oral Anticoagulation Therapy Improves Outcome in Patients with Chronic Renal Insufficiency.

Oral anticoagulation (OAC) is effective at preventing and treating thromboses and thromboembolism in patients with normal renal function. We aimed to research the impact of severe renal failure (RF) on patient outcome and to determine the potential benefit of caring for these patients in a specialized coagulation service (CS). A total of 1516 usual medical care patients and 756 CS-managed patients of the thrombEVAL multicenter (21 centers), prospective, cohort study (NCT01809015) were analyzed in a 3-year follow-up. Patients with RF (serum creatinine >3 mg/dL, no renal replacement therapy) were compared to patients without RF in usual care and a CS. The fluctuations in the international normalized ratios were significantly lower in CS-managed patients, and regardless of treatment in usual care or a CS, the time in therapeutic range was significantly lower in RF patients. Cox regression-adjusted hazard ratios for long-term outcome (1.5, 95% CI: 1.22-1.83, p < 0.001), death (1.62, CI: 1.27-2.08, p < 0.001), and hospitalization (1.21, CI: 1.02-1.44, p = 0.032) were significantly higher in RF patients in usual care. Furthermore, there was a trend of more bleeding events in RF patients. CS-treated patients had significantly lower adjusted hazard ratios for death (0.24, CI: 0.14-0.39, p < 0.001), hospitalizations (0.41, CI: 0.34-0.5, p < 0.001), clinically relevant bleeding (0.29, CI: 0.18-0.47, p < 0.001), and major bleeding (0.33, CI: 0.18-0.59, p < 0.001). Thus, patients who required oral anticoagulation therapy benefitted significantly from being managed in a specialized coagulation service, regardless of their renal function.

Telemedicine-Based Specialized Care Improves the Outcome of Anticoagulated Individuals with Venous Thromboembolism-Results from the thrombEVAL Study.

Venous thromboembolism (VTE) is a life-threatening disease with risk of recurrence. Oral anticoagulation (OAC) with vitamin K antagonists (VKA) is effective to prevent thromboembolic recurrence. We aimed to investigate the quality of OAC of VTE patients in regular medical care (RMC) compared to a telemedicine-based coagulation service (CS). The thrombEVAL study (NCT01809015) is a prospective, multi-center study to investigate OAC treatment (recruitment: January 2011-March 2013). Patients were evaluated using clinical visits, computer-assisted personal interviews, self-reported data and laboratory measurements according to standard operating procedures. Overall, 360 patients with VTE from RMC and 254 from CS were included. Time in therapeutic range (TTR) was higher in CS compared to RMC (76.9% (interquartile range [IQR] 63.2-87.1%) vs. 69.5% (52.3-85.6%), p < 0.001). Crude rate of thromboembolic events (rate ratio [RR] 11.33 (95% confidence interval [CI] 1.85-465.26), p = 0.0015), clinically relevant bleeding (RR 6.80 (2.52-25.76), p < 0.001), hospitalizations (RR 2.54 (1.94-3.39), p < 0.001) and mortality under OAC (RR 5.89 (2.40-18.75), p < 0.001) were consistently higher in RMC compared with CS. Patients in RMC had higher risk for primary outcome (clinically relevant bleedings, thromboembolic events and mortality, hazard ratio [HR] 5.39 (95%CI 2.81-10.33), p < 0.0001), mortality (HR 5.54 (2.22-13.84), p = 0.00025), thromboembolic events (HR 6.41 (1.51-27.24), p = 0.012), clinically relevant bleeding (HR 5.31 (1.89-14.89), p = 0.0015) and hospitalization (HR 1.84 (1.34-2.55), p = 0.0002). Benefits of CS care were still observed after adjusting for comorbidities and TTR. In conclusion, anticoagulation quality and outcome of VTE patients undergoing VKA treatment was significantly better in CS than in RMC. Patients treated in CS had lower rates of adverse events, hospitalizations and lower mortality. CS was prognostically relevant, beyond providing advantages of improved international ratio (INR) monitoring.