Somatic symptom profile in patients with chronic heart failure with and without depressive comorbidity.

Background: Patients with chronic heart failure (CHF) frequently suffer from depressive comorbidity. CHF and depressive comorbidity can cause somatic symptoms. The correct attribution of somatic symptoms is important. Thus, we aimed to assess potential differences in somatic symptom severity between CHF patients with and without depressive comorbidity. Methods: We evaluated depressive comorbidity using the Patient Health Questionnaire-9 (PHQ-9), somatic symptom severity with the Patient Health Questionnaire-15 (PHQ-15), and sociodemographic and medical variables in 308 CHF outpatients. To compare somatic symptom severity between CHF patients with and without depressive comorbidity, we conducted item-level analyses of covariance. Results: Of the 308 participating patients, 93 (30.3%) met the PHQ-9 criteria for depressive comorbidity. These patients did not differ from those without depressive comorbidity with regard to age, sex, left ventricular function, and multimorbidity. Patients with depressive comorbidity scored significantly higher on ten out of thirteen PHQ-15 items than patients without depressive comorbidity. The largest effect sizes (0.71-0.80) were shown for symptoms of headache, chest pain, shortness of breath, and palpitations, and the latter three were potentially attributable to heart failure. Conclusions: Among patients with CHF, somatic symptoms are more pronounced in those with depressive comorbidity than those without depressive comorbidity. This finding is especially true for cardiac symptoms independent of CHF severity. The potential interpretation of somatic symptoms as correlates of depressive comorbidity must be recognized in clinical practice.

Generalized anxiety is a predictor of impaired quality of life in patients with atrial fibrillation: Findings from the prospective observational ARENA study.

OBJECTIVE: Atrial fibrillation (AF) is associated with impaired health-related quality of life (HRQoL), an increased risk of morbidity, and mortality. Traditional AF-related outcomes (e.g., AF recurrence) primarily demonstrate the physiological benefits of AF management but do not focus on the benefits experienced subjectively by the patient (i.e., patient-reported outcomes), which have been suggested as optimal endpoints in AF intervention studies. The aim of this study is to identify medical and psychological factors associated with impaired HRQoL at 1-year follow-up. METHODS: Using data from the prospective observational multicenter ARENA study in patients with AF, we analyzed associations between medical factors, anxiety, and HRQoL at 1-year follow-up assessed using 5-level EuroQoL-5D. RESULTS: In 1353 AF patients (mean age 71.4 ± 10.3 years, 33.8% female), none of the medical predictors (e.g., heart disease) or history of cardioversion were associated with HRQoL at the 1-year follow-up. Higher generalized anxiety (ß = -0.114, p < .001) but not cardiac anxiety (ß = -0.006, p = .809) at baseline predicted decreased HRQoL, independent of confounding variables and patients' medical status. Furthermore, the worsening of patients' generalized anxiety was associated with decreased HRQoL (ß = -0.091, p < .001). In contrast, the improvement of generalized anxiety over time predicted higher HRQoL (ß = 0.097, p < .001). Finally, the worsening of patients' cardiac anxiety over time was associated with decreased HRQoL (ß = -0.081, p < .001). CONCLUSION: Our results highlight the importance of anxiety as a predictor of future HRQoL in patients with AF. Additional studies to examine the impact of anxiety treatment on HRQoL in this population are needed. CLINICAL TRIAL REGISTRATION: The investigators registered on ClinicalTrials.gov (NCT02978248) on November 30, 2016 https://clinicaltrials.gov/ct2/show/NCT02978248.

Predictors of persistent symptoms after mRNA SARS-CoV-2 vaccine-related myocarditis (myovacc registry).

Aims: Epidemiological surveillance has raised safety concerns for mRNA SARS-CoV-2-vaccination-related myocarditis. We aimed to analyze epidemiological, clinical and imaging findings associated with clinical outcomes in these patients in an international multi-center registry (NCT05268458). Methods and results: Patients with clinical and CMR diagnosis of acute myocarditis within 30 days after mRNA SARS-CoV-2-vaccination were included from five centers in Canada and Germany between 05/21 and 01/22. Clinical follow-up on persistent symptoms was collected. We enrolled 59 patients (80% males, mean age 29 years) with CMR-derived mild myocarditis (hs-Troponin-T 552 [249-1,193] ng/L, CRP 28 [13-51] mg/L; LVEF 57 ± 7%, LGE 3 [2-5] segments). Most common symptoms at baseline were chest pain (92%) and dyspnea (37%). Follow-up data from 50 patients showed overall symptomatic burden improvement. However, 12/50 patients (24%, 75% females, mean age 37 years) reported persisting symptoms (median interval 228 days) of chest pain (n = 8/12, 67%), dyspnea (n = 7/12, 58%), with increasing occurrence of fatigue (n = 5/12, 42%) and palpitations (n = 2/12, 17%). These patients had initial lower CRP, lower cardiac involvement in CMR, and fewer ECG changes. Significant predictors of persisting symptoms were female sex and dyspnea at initial presentation. Initial severity of myocarditis was not associated with persisting complaints. Conclusion: A relevant proportion of patients with mRNA SARS-CoV-2-vaccination-related myocarditis report persisting complaints. While young males are usually affected, patients with persisting symptoms were predominantly females and older. The severity of the initial cardiac involvement not predicting these symptoms may suggest an extracardiac origin.

Comparison of Investigator-Reported and Centrally Adjudicated Heart Failure Outcomes in the EMPEROR-Reduced Trial.

BACKGROUND: There is limited published information on outcome adjudication in heart failure (HF). OBJECTIVES: The authors sought to compare investigator reports (IRs) to a Clinical Events Committee (CEC) and the impact of SCTI (Standardized Clinical Trial Initiative) criteria. METHODS: In the EMPEROR-Reduced trial, the authors compared IRs to the CEC for concordance; treatment effect on primary composite outcome events; and the components first event hospitalization primarily for HF or cardiovascular mortality (CVM), prognosis after hospitalization for heart failure (HHF), total HHFs, and trial duration with and without SCTI criteria. RESULTS: The CEC confirmed 76.3% of IR events for the primary outcome (CVM: 89.1%; HHF: 73.7%). The HR for treatment effect did not differ between adjudication methods for the primary outcome (IR: 0.75 [95% CI: 0.66-0.85]; CEC: 0.75 [95% CI: 0.65-0.86]), its components, or total HHFs. The prognosis after first HHF for all-cause mortality and CVM also did not differ between IR or CEC. Interestingly, IR primary HHF with different CEC primary cause had the highest subsequent fatal event rate. Full SCTI criteria were present in 90% of CEC HHFs-with a similar treatment effect to non-SCTI. The IR primary event reached the protocol target number (841) 3 months earlier than CEC (4 months with full SCTI criteria). CONCLUSIONS: Investigator adjudication is an alternative to a CEC with similar accuracy and faster event accumulation. The use of granular (SCTI) criteria did not improve trial performance. Finally, our data suggest that consideration be given to broadening the HHF definition to include "for or with" worsening disease. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).

Case report: Case series of isolated acute pericarditis after SARS-CoV-2 vaccinations.

During the worldwide ongoing immunization campaign against SARS-CoV-2, growing data on very rare but potentially harmful side effects of such vaccines arise since approval trials have not been adequately powered to detect those events. Besides the already reported vaccine-related myocarditis, which primarily occurs in young male individuals, our attention was recently drawn to a series of older male and female patients, who were referred to our institutions with isolated acute pericarditis without myocardial damage, shortly after SARS-CoV-2 vaccination. We describe a series of five adult patients presenting with chest pain, shortness of breath and isolated pericarditis with and without pericardial effusion after SARS-CoV-2 vaccination. All patients underwent echocardiography and cardiac magnetic resonance, and the corresponding findings, including late gadolinium enhancement (LGE) and T1 and T2 mapping are reported herein. To our knowledge, such cases have not been systematically reported in the current literature so far.

Symptom Severity and Health-Related Quality of Life in Patients with Atrial Fibrillation: Findings from the Observational ARENA Study.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with impaired health-related quality of life (HRQoL), high symptom severity, and poor cardiovascular outcomes. Both clinical and psychological factors may contribute to symptom severity and HRQoL in AF. METHODS: Using data from the observational Atrial Fibrillation Rhine-Neckar Region (ARENA) trial, we identified medical and psychosocial factors associated with AF-related symptom severity using European Heart Rhythm Association symptom classification and HRQoL using 5-level EuroQoL- 5D. RESULTS: In 1218 AF patients (mean age 71.1 ± 10.5 years, 34.5% female), female sex (OR 3.7, p < 0.001), preexisting coronary artery disease (CAD) (OR 1.7, p = 0.020), a history of cardioversion (OR 1.4, p = 0.041), cardiac anxiety (OR 1.2; p < 0.001), stress from noise (OR 1.4, p = 0.005), work-related stress (OR 1.3, p = 0.026), and sleep disturbance (OR 1.2, p = 0.016) were associated with higher AF-related symptom severity. CAD (ß = -0.23, p = 0.001), diabetes mellitus (ß = -0.25, p < 0.001), generalized anxiety (ß = -0.30, p < 0.001), cardiac anxiety (ß = -0.16, p < 0.001), financial stress (ß = -0.11, p < 0.001), and sleep disturbance (ß = 0.11, p < 0.001) were associated with impaired HRQoL. CONCLUSIONS: Psychological characteristics, preexisting CAD, and diabetes may play an important role in the identification of individuals at highest risk for impaired HRQoL and high symptom severity in patients with AF.

Effect of Empagliflozin on Worsening Heart Failure Events in Patients With Heart Failure and Preserved Ejection Fraction: EMPEROR-Preserved Trial.

BACKGROUND: Empagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure with preserved ejection fraction, but additional data are needed about its effect on inpatient and outpatient heart failure events. METHODS: We randomly assigned 5988 patients with class II through IV heart failure with an ejection fraction of >40% to double-blind treatment with placebo or empagliflozin (10 mg once daily), in addition to usual therapy, for a median of 26 months. We prospectively collected information on inpatient and outpatient events reflecting worsening heart failure and prespecified their analysis in individual and composite end points. RESULTS: Empagliflozin reduced the combined risk of cardiovascular death, hospitalization for heart failure, or an emergency or urgent heart failure visit requiring intravenous treatment (432 versus 546 patients [empagliflozin versus placebo, respectively]; hazard ratio, 0.77 [95% CI, 0.67-0.87]; P<0.0001). This benefit reached statistical significance at 18 days after randomization. Empagliflozin reduced the total number of heart failure hospitalizations that required intensive care (hazard ratio, 0.71 [95% CI, 0.52-0.96]; P=0.028) and the total number of all hospitalizations that required a vasopressor or positive inotropic drug (hazard ratio, 0.73 [95% CI, 0.55-0.97]; P=0.033). Compared with patients in the placebo group, fewer patients in the empagliflozin group reported outpatient intensification of diuretics (482 versus 610; hazard ratio, 0.76 [95% CI, 0.67-0.86]; P<0.0001), and patients assigned to empagliflozin were 20% to 50% more likely to have a better New York Heart Association functional class, with significant effects at 12 weeks that were maintained for at least 2 years. The benefit on total heart failure hospitalizations was similar in patients with an ejection fraction of >40% to <50% and 50% to <60%, but was attenuated at higher ejection fractions. CONCLUSIONS: In patients with heart failure with preserved ejection fraction, empagliflozin produced a meaningful, early, and sustained reduction in the risk and severity of a broad range of inpatient and outpatient worsening heart failure events. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

Effect of Empagliflozin on the Clinical Stability of Patients With Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial.

BACKGROUND: Empagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, with or without diabetes, but additional data are needed about the effect of the drug on inpatient and outpatient events that reflect worsening heart failure. METHODS: We randomly assigned 3730 patients with class II to IV heart failure with an ejection fraction of ≤40% to double-blind treatment with placebo or empagliflozin (10 mg once daily), in addition to recommended treatments for heart failure, for a median of 16 months. We prospectively collected information on inpatient and outpatient events reflecting worsening heart failure and prespecified their analysis in individual and composite end points. RESULTS: Empagliflozin reduced the combined risk of death, hospitalization for heart failure or an emergent/urgent heart failure visit requiring intravenous treatment (415 versus 519 patients; empagliflozin versus placebo, respectively; hazard ratio [HR], 0.76; 95% CI, 0.67-0.87; P<0.0001). This benefit reached statistical significance at 12 days after randomization. Empagliflozin reduced the total number of heart failure hospitalizations that required intensive care (HR, 0.67; 95% CI, 0.50-0.90; P=0.008) and that required a vasopressor or positive inotropic drug or mechanical or surgical intervention (HR, 0.64; 95% CI, 0.47-0.87; P=0.005). As compared with placebo, fewer patients in the empagliflozin group reported intensification of diuretics (297 versus 414 [HR, 0.67; 95% CI, 0.56-0.78; P<0.0001]). Additionally, patients assigned to empagliflozin were 20% to 40% more likely to experience an improvement in New York Heart Association functional class and were 20% to 40% less likely to experience worsening of New York Heart Association functional class, with statistically significant effects that were apparent 28 days after randomization and maintained during long-term follow-up. The risk of any inpatient or outpatient worsening heart failure event in the placebo group was high (48.1 per 100 patient-years of follow-up), and it was reduced by empagliflozin (HR, 0.70; 95% CI, 0.63-0.78; P<0.0001). CONCLUSIONS: In patients with heart failure and a reduced ejection fraction, empagliflozin reduced the risk and total number of inpatient and outpatient worsening heart failure events, with benefits seen early after initiation of treatment and sustained for the duration of double-blind therapy. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

A multi-vendor, multi-center study on reproducibility and comparability of fast strain-encoded cardiovascular magnetic resonance imaging.

Myocardial strain is a convenient parameter to quantify left ventricular (LV) function. Fast strain-encoding (fSENC) enables the acquisition of cardiovascular magnetic resonance images for strain-measurement within a few heartbeats during free-breathing. It is necessary to analyze inter-vendor agreement of techniques to determine strain, such as fSENC, in order to compare existing studies and plan multi-center studies. Therefore, the aim of this study was to investigate inter-vendor agreement and test-retest reproducibility of fSENC for three major MRI-vendors. fSENC-images were acquired three times in the same group of 15 healthy volunteers using 3 Tesla scanners from three different vendors: at the German Heart Institute Berlin, the Charité University Medicine Berlin-Campus Buch and the Theresien-Hospital Mannheim. Volunteers were scanned using the same imaging protocol composed of two fSENC-acquisitions, a 15-min break and another two fSENC-acquisitions. LV global longitudinal and circumferential strain (GLS, GCS) were analyzed by a trained observer (Myostrain 5.0, Myocardial Solutions) and for nine volunteers repeatedly by another observer. Inter-vendor agreement was determined using Bland-Altman analysis. Test-retest reproducibility and intra- and inter-observer reproducibility were analyzed using intraclass correlation coefficient (ICC) and coefficients of variation (CoV). Inter-vendor agreement between all three sites was good for GLS and GCS, with biases of 0.01-1.88%. Test-retest reproducibility of scans before and after the break was high, shown by ICC- and CoV values of 0.63-0.97 and 3-9% for GLS and 0.69-0.82 and 4-7% for GCS, respectively. Intra- and inter-observer reproducibility were excellent for both parameters (ICC of 0.77-0.99, CoV of 2-5%). This trial demonstrates good inter-vendor agreement and test-retest reproducibility of GLS and GCS measurements, acquired at three different scanners from three different vendors using fSENC. The results indicate that it is necessary to account for a possible bias (< 2%) when comparing strain measurements of different scanners. Technical differences between scanners, which impact inter-vendor agreement, should be further analyzed and minimized.DRKS Registration Number: 00013253.Universal Trial Number (UTN): U1111-1207-5874.

Significance of psychosocial factors in cardiology: update 2018 : Position paper of the German Cardiac Society.

BACKGROUND: Psychosocial factors in cardiovascular diseases are increasingly acknowledged by patients, health care providers and payer organizations. Due to the rapidly increasing body of evidence, the German Cardiac Society has commissioned an update of its 2013 position paper on this topic. The German version was published in 2018 and the current manuscript is an extended translation of the original version. METHODS: This position paper provides a synopsis of the state of knowledge regarding psychosocial factors in the most relevant cardiovascular diseases and gives recommendations with respect to their consideration in clinical practice. RESULTS: Psychosocial factors such as low socioeconomic status, acute and chronic stress, depression, anxiety and low social support are associated with an unfavorable prognosis. Psychosocial problems and mental comorbidities should be assessed routinely to initiate targeted diagnostics and treatment. For all patients, treatment should consider age and gender differences as well as individual patient preferences. Multimodal treatment concepts should comprise education, physical exercise, motivational counseling and relaxation training or stress management. In cases of mental comorbidities, brief psychosocial interventions by primary care providers or cardiologists, regular psychotherapy and/or medications should be offered. While these interventions have positive effects on psychological symptoms, robust evidence for possible effects on cardiac outcomes is still lacking. CONCLUSIONS: For coronary heart disease, chronic heart failure, arterial hypertension, and some arrhythmias, there is robust evidence supporting the relevance of psychosocial factors, pointing to a need for considering them in cardiological care. However, there are still shortcomings in implementing psychosocial treatment, and prognostic effects of psychotherapy and psychotropic drugs remain uncertain. There is a need for enhanced provider education and more treatment trials.

Anxiety and self-care behaviour in patients with chronic systolic heart failure: A multivariate model.

BACKGROUND: While comprehensive evidence exists regarding negative effects of depression on self-care behaviours in patients with chronic heart failure (CHF), the relation between anxiety and self-care behaviours in patients with CHF is not clear. The aim of this study was to analyse the interactions between anxiety, depression and self-care behaviours in patients with CHF. METHODS: The self-care behaviour of CHF outpatients was measured using the European Heart Failure Self-care Behaviour Scale (EHFScBS). The Patient Health Questionnaire (PHQ) was used to assess anxiety, the PHQ-9 was used to measure depression severity. Differences between patients with and without anxiety were assessed with the respective tests. Associations between anxiety, self-care and other predictors were analysed using linear regressions. RESULTS: Of the 308 participating patients, 35 (11.4%) fulfilled the PHQ criteria for an anxiety disorder. These patients took antidepressants more frequently (11.8% versus 2.3%, p = .02), had had more contacts with their general practitioner within the last year (11.8 ± 16.1 versus 6.7 ± 8.6, p = .02), and had a higher PHQ-9 depression score (12.9 ± 5.7 versus 6.5 ± 4.7, p < .01) than patients without anxiety disorder. Anxiety and self-care were negatively associated (ß = -0.144, r2 = 0.021, p = 0.015). The explanation of variance was augmented in a multivariate regression with the predictors age, sex, education, living with a partner, and New York Heart Association (NYHA) class ( r2 = 0.098) when anxiety was added ( r2 = 0.112). Depression further increased the explanation of variance (ß = -0.161, r2 = 0.131, p = 0.019). CONCLUSIONS: Anxiety is negatively associated with self-care behaviour in patients with CHF. However, this effect disappears behind the stronger influence of depression on self-care. The consideration of mental comorbidities in patients with CHF is important.

Depletion of cardiac catecholamine stores impairs cardiac norepinephrine re-uptake by downregulation of the norepinephrine transporter.

In heart failure (HF), a disturbed cardiac norepinephrine (NE) homeostasis is characterized by depleted cardiac NE stores, impairment of the cardiac NE re-uptake by the neuronal norepinephrine transporter (NET) and enhanced cardiac NE net release. Reduced cardiac NE content appears to be caused by enhanced cardiac NE net release from sympathetic neurons in HF, triggered by neurohumoral activation. However, it remains unclear whether reduced NE itself has an impact on cardiac NE re-uptake, independent of neurohumoral activation. Here, we evaluated whether depletion of cardiac NE stores alone can regulate cardiac NE re-uptake. Treatment of Wistar rats with reserpine (5 mg/kg/d) for one (1d) or five days (5d) resulted in markedly reduced cardiac NE content, comparable to NE stores in experimental HF due to pressure overload. In order to assess cardiac NE re-uptake, the specific cardiac [3H]-NE uptake via the NET in a Langendorff preparation was measured. Reserpine treatment led to decreased NE re-uptake at 1d and 5d compared to saline treatment. Expression of tyrosine hydroxylase (TH), the rate-limiting enzyme of the NE synthesis, was elevated in left stellate ganglia after reserpine. Mechanistically, measurement of NET mRNA expression in left stellate ganglia and myocardial NET density revealed a post-transcriptional downregulation of the NET by reserpine. In summary, present data demonstrate that depletion of cardiac NE stores alone is sufficient to impair cardiac NE re-uptake via downregulation of the NET, independent of systemic neurohumoral activation. Knowledge about the regulation of the cardiac NE homeostasis may offer novel therapeutic strategies in HF.

Effect of Escitalopram on All-Cause Mortality and Hospitalization in Patients With Heart Failure and Depression: The MOOD-HF Randomized Clinical Trial.

IMPORTANCE: Depression is frequent in patients with heart failure and is associated with adverse clinical outcomes. Long-term efficacy and safety of selective serotonin reuptake inhibitors in these patients are unknown. OBJECTIVE: To determine whether 24 months of treatment with escitalopram improves mortality, morbidity, and mood in patients with chronic systolic heart failure and depression. DESIGN, SETTING, AND PARTICIPANTS: The Effects of Selective Serotonin Re-Uptake Inhibition on Morbidity, Mortality, and Mood in Depressed Heart Failure Patients (MOOD-HF) study was a double-blind, placebo-controlled randomized clinical trial conducted at 16 tertiary medical centers in Germany. Between March 2009 and February 2014, patients at outpatient clinics with New York Heart Association class II-IV heart failure and reduced left ventricular ejection fraction (<45%) were screened for depression using the 9-item Patient Health Questionnaire. Patients with suspected depression were then invited to undergo a Structured Clinical Interview based on the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) to establish the diagnosis. INTERVENTIONS: Patients were randomized 1:1 to receive escitalopram (10-20 mg) or matching placebo in addition to optimal heart failure therapy. Study duration was 24 months. MAIN OUTCOMES AND MEASURES: The composite primary outcome was time to all-cause death or hospitalization. Prespecified secondary outcomes included safety and depression severity at 12 weeks of treatment (including the titration period), which were determined using the 10-item Montgomery-Åsberg Depression Rating Scale (total possible score, 0 to 60; higher scores indicate more severe depression). RESULTS: A total of 372 patients (mean age, 62 years; 24% female) were randomized and had taken at least 1 dose of study medication when the data and safety monitoring committee recommended the trial be stopped early. During a median participation time of 18.4 months (n = 185) for the escitalopram group and 18.7 months (n = 187) for the placebo group, the primary outcome of death or hospitalization occurred in 116 (63%) patients and 119 (64%) patients, respectively (hazard ratio, 0.99 [95% CI, 0.76 to 1.27]; P = .92). The mean Montgomery-Åsberg Depression Rating Scale sum score changed from 20.2 at baseline to 11.2 at 12 weeks in the escitalopram group and from 21.4 to 12.5 in the placebo group (between-group difference, -0.9 [95% CI,-2.6 to 0.7]; P = .26). Safety parameters were comparable between groups. CONCLUSIONS AND RELEVANCE: In patients with chronic heart failure with reduced ejection fraction and depression, 18 months of treatment with escitalopram compared with placebo did not significantly reduce all-cause mortality or hospitalization, and there was no significant improvement in depression. These findings do not support the use of escitalopram in patients with chronic systolic heart failure and depression. TRIAL REGISTRATION: isrctn.com Identifier: ISRCTN33128015.

The Hospitalization Burden and Post-Hospitalization Mortality Risk in Heart Failure With Preserved Ejection Fraction: Results From the I-PRESERVE Trial (Irbesartan in Heart Failure and Preserved Ejection Fraction).

OBJECTIVES: The aim of this study was to investigate prognosis in patients with heart failure (HF) with preserved ejection fraction and the causes of hospitalization and post-hospitalization mortality. BACKGROUND: Although hospitalizations in patients with HF with preserved ejection fraction are common, there are limited data from clinical trials on the causes of admission and the influence of hospitalizations on subsequent mortality risk. METHODS: Patients (n = 4,128) with New York Heart Association functional class II to IV HF and left ventricular ejection fractions >45% were enrolled in I-PRESERVE (Irbesartan in Heart Failure and Preserved Ejection Fraction). A blinded events committee adjudicated cardiovascular hospitalizations and all deaths using predefined and standardized definitions. The risk for death after HF, any-cause, or non-HF hospitalization was assessed using time-dependent Cox proportional hazard models. RESULTS: A total of 2,278 patients had 5,863 hospitalizations during the 49 months of follow-up, of which 3,585 (61%) were recurrent hospitalizations. For any-cause hospitalizations, 26.5% of patients died during follow-up, with an incident mortality rate of 11.1 deaths per 100 patient-years (PYs) and an adjusted hazard ratio of 5.32 (95% confidence interval: 4.21 to 6.23). Overall, 53.6% of hospitalizations were classified as cardiovascular and 43.7% as noncardiovascular, with 2.7% not classifiable. HF was the largest single cause of initial (17.6%) and overall (21.1%) hospitalizations, although, after HF hospitalization, a substantially higher proportion of readmissions were due to primary HF causes (40%). HF hospitalization occurred in 685 patients, with 41% deaths during follow-up, an incident mortality rate of 19.3 deaths per 100 PYs. The adjusted hazard ratio was 2.93 (95% confidence interval: 2.40 to 3.57) relative to patients who were not hospitalized for HF and was greater in those with longer durations of hospitalization. There were 1,593 patients with only non-HF hospitalizations, 21% of whom died during follow-up, with an incident mortality rate of 8.7 deaths per 100 PYs and an adjusted hazard ratio of 4.25 (95% confidence interval: 3.27 to 5.32). The risk for death was highest in the first 30 days and declined over time for all hospitalization categories. Patients not hospitalized for HF or for any cause had observed incident mortality rates of 3.8 and 1.3 deaths per 100 PYs, respectively. CONCLUSIONS: In I-PRESERVE, HFpEF patients hospitalized for any reason, and especially for HF, were at high risk for subsequent death, particularly early. The findings support the need for careful attention in the post-discharge time period including attention to comorbid conditions. Among those hospitalized for HF, the high mortality rate and increased proportion of readmissions due to HF (highest during the first 30 days), suggest that this group would be an appropriate target for investigation of new interventions.

Essential role of sympathetic endothelin A receptors for adverse cardiac remodeling.

In preclinical studies, endothelin receptor A (ETA) antagonists (ETAi) attenuated the progression of heart failure (HF). However, clinical HF trials failed to demonstrate beneficial effects of ETAi. These conflicting data may be explained by the possibility that established HF drugs such as adrenergic receptor blockers interfered with the mechanism of ETAi action in clinical trials. Here we report that mice lacking ETA only in sympathetic neurons (SN-KO) showed less adverse structural remodeling and cardiac dysfunction in response to pathological pressure overload induced by transverse aortic constriction (TAC). In contrast, mice lacking ETA only in cardiomyocytes (CM-KO) were not protected. TAC led to a disturbed sympathetic nerve function as measured by cardiac norepinephrine (NE) tissue levels and [(124)I]-metaiodobenzylguanidine-PET, which was prevented in SN-KO. In a rat model of HF, ETAi improved cardiac and sympathetic nerve function. In cocultures of cardiomyocytes (CMs) and sympathetic neurons (SNs), endothelin-1 (ET1) led to a massive NE release and exaggerated CM hypertrophy compared with CM monocultures. ETA-deficient CMs gained a hypertrophic response through wild-type SNs, but ETA-deficient SNs failed to mediate exaggerated CM hypertrophy. Furthermore, ET1 mediated its effects indirectly via NE in CM-SN cocultures through adrenergic receptors and histone deacetylases, resulting in activation of the prohypertrophic transcription factor myocyte enhancer factor 2. In conclusion, sympathetic ETA amplifies ET1 effects on CMs through adrenergic signaling pathways. Thus, antiadrenergic therapies may blunt potentially beneficial effects of ETAi. Taken together, this may indicate that patients with ß blocker intolerance or disturbed sympathetic nerve function could be evaluated for a potential benefit from ETAi.

Aldosterone augments Na+-induced reduction of cardiac norepinephrine reuptake.

Impairment of the cardiac norepinephrine (NE) reuptake by the neuronal NE transporter contributes to enhanced cardiac NE net release in congestive heart failure. Elevated plasma levels of aldosterone (AL) promote sympathetic overstimulation in failing hearts by unclear mechanisms. Our aim was to evaluate if elevated AL and/or alterations in Na(+) intake regulate cardiac NE reuptake. To test the effects of AL and Na(+) on cardiac NE reuptake, Wistar rats were fed a normal-salt (NS) diet (0.2% NaCl), a low-salt (LS) diet (0.015% NaCl), or a high-salt (HS) diet (8% NaCl). Another group of animals received AL infusion alone (0.75 µg/h) or AL infusion plus HS diet. Specific cardiac [(3)H]NE uptake via the NE transporter in a Langendorff preparation and AL plasma levels were measured at different time points between 5 and 42 days of treatment. To compare these findings from healthy animals with a disease model, Dahl salt-sensitive rats were investigated as a model of congestive heart failure with endogenously elevated AL. In summary, neither exogenous nor endogenous elevations of AL alone were sufficient to reduce cardiac NE reuptake. Only the HS diet induced a reduction of NE reuptake by 26%; additional infusion of AL augmented this effect to a further reduction of NE reuptake by 36%. In concordance, Dahl salt-sensitive rats treated with a HS diet displayed elevated AL and a marked reduction of NE reuptake. We conclude that exogenous or endogenous AL elevations alone do not reduce cardiac NE reuptake, but AL serves as an additional factor that negatively regulates cardiac NE reuptake in concert with HS intake.

Position paper on the importance of psychosocial factors in cardiology: Update 2013.

BACKGROUND: The rapid progress of psychosomatic research in cardiology and also the increasing impact of psychosocial issues in the clinical daily routine have prompted the Clinical Commission of the German Heart Society (DGK) to agree to an update of the first state of the art paper on this issue which was originally released in 2008. METHODS: The circle of experts was increased, general aspects were implemented and the state of the art was updated. Particular emphasis was dedicated to coronary heart diseases (CHD), heart rhythm diseases and heart failure because to date the evidence-based clinical knowledge is most advanced in these particular areas. Differences between men and women and over the life span were considered in the recommendations as were influences of cognitive capability and the interactive and synergistic impact of classical somatic risk factors on the affective comorbidity in heart disease patients. RESULTS: A IA recommendation (recommendation grade I and evidence grade A) was given for the need to consider psychosocial risk factors in the estimation of coronary risks as etiological and prognostic risk factors. Furthermore, for the recommendation to routinely integrate psychosocial patient management into the care of heart surgery patients because in these patients, comorbid affective disorders (e.g. depression, anxiety and post-traumatic stress disorder) are highly prevalent and often have a malignant prognosis. A IB recommendation was given for the treatment of psychosocial risk factors aiming to prevent the onset of CHD, particularly if the psychosocial risk factor is harmful in itself (e.g. depression) or constrains the treatment of the somatic risk factors. Patients with acute and chronic CHD should be offered anti-depressive medication if these patients suffer from medium to severe states of depression and in this case medication with selective reuptake inhibitors should be given. In the long-term course of treatment with implanted cardioverter defibrillators (ICDs) a subjective health technology assessment is warranted. In particular, the likelihood of affective comorbidities and the onset of psychological crises should be carefully considered. CONCLUSIONS: The present state of the art paper presents an update of current empirical evidence in psychocardiology. The paper provides evidence-based recommendations for the integration of psychosocial factors into cardiological practice and highlights areas of high priority. The evidence for estimating the efficiency for psychotherapeutic and psychopharmacological interventions has increased substantially since the first release of the policy document but is, however, still weak. There remains an urgent need to establish curricula for physician competence in psychodiagnosis, communication and referral to ensure that current psychocardiac knowledge is translated into the daily routine.

Potentially modifiable correlates of functional status in patients with chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) patients suffer from multiple and agonizing symptoms like shortness of breath and reduced functional status, the latter of which is usually assessed using New York Heart Association (NYHA) functional class. PURPOSE: In order to identify potentially modifiable factors of reduced functional status in patients with CHF, we investigated somatic and psychosocial correlates of NYHA functional class. We subsequently compared the results to correlates of left ventricular ejection fraction (LVEF) as an objective parameter of disease severity. METHODS: The cross-sectional study (n = 314) was part of the German Heart Failure Network. Data were analysed using a logistic regression modelling process. RESULTS: In the final regression model, NYHA functional class was only significantly associated with depression (odds ratio (OR) = 1.18; 95% confidence interval (CI) = 1.09-1.27) and multimorbidity (OR = 1.17; 95% CI = 1.04-1.32). LVEF was associated with amino-terminal pro-brain natriuretic peptide (NT-proBNP) (OR = 0.60; 95% CI = 0.44-0.82), aetiology of CHF (OR = 2.08; 95% CI = 1.11-3.90), and smoking (OR = 2.21; 95% CI = 1.25-3.91). CONCLUSIONS: Whereas LVEF was not related to depression, our data revealed a close association between functional status (as assessed by NYHA functional class) and depression in patients with CHF, even after adjusting for cardiac and socio-demographic variables. Different forms of underlying causal mechanisms could be suspected; it appears promising to further investigate this specific interaction. In any event, pending further investigation, our results underscore the need to examine CHF patients with respect to both somatic symptom burden and potential depressive disorders.