Hemodynamic Effects of Cyclic Guanosine Monophosphate-Dependent Signaling Through ß3 Adrenoceptor Stimulation in Patients With Advanced Heart Failure: A Randomized Invasive Clinical Trial.

BACKGROUND: ß3-AR (ß3-adrenergic receptor) stimulation improved systolic function in a sheep model of systolic heart failure (heart failure with reduced ejection fraction [HFrEF]). Exploratory findings in patients with New York Heart Association functional class II HFrEF treated with the ß3-AR-agonist mirabegron supported this observation. Here, we measured the hemodynamic response to mirabegron in patients with severe HFrEF. METHODS: In this randomized, double-blind, placebo-controlled trial we assigned patients with New York Heart Association functional class III-IV HFrEF, left ventricular ejection fraction <35% and increased NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels to receive mirabegron (300 mg daily) or placebo orally for a week, as add on to recommended HF therapy. Invasive hemodynamic measurements during rest and submaximal exercise at baseline, 3 hours after first study dose and repeated after 1 week's treatment were obtained. Predefined parameters for analyses were changes in cardiac- and stroke volume index, pulmonary and systemic vascular resistance, heart rate, and blood pressure. RESULTS: We randomized 22 patients (age 66±11 years, 18 men, 16, New York Heart Association functional class III), left ventricular ejection fraction 20±7%, median NT-proBNP 1953 ng/L. No significant changes were seen after 3 hours, but after 1 week, there was a significantly larger increase in cardiac index in the mirabegron group compared with the placebo group (mean difference, 0.41 [CI, 0.07-0.75] L/min/BSA; P=0.039). Pulmonary vascular resistance decreased significantly more in the mirabegron group compared with the placebo group (-1.6 [CI, -0.4 to -2.8] Wood units; P=0.02). No significant differences were seen during exercise. There were no differences in changes in heart rate, systemic vascular resistance, blood pressure, or renal function between groups. Mirabegron was well-tolerated. CONCLUSIONS: Oral treatment with the ß3-AR-agonist mirabegron for 1 week increased cardiac index and decreased pulmonary vascular resistance in patients with moderate to severe HFrEF. Mirabegron may be useful in patients with worsening or terminal HF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: 2016-002367-34.

Allergen immunotherapy effectively reduces the risk of exacerbations and lower respiratory tract infections in both seasonal and perennial allergic asthma: a nationwide epidemiological study.

BACKGROUND: Allergic asthma is associated with increased risk of respiratory tract infections and exacerbations. It remains unclear whether this susceptibility is conditioned by seasonal or by perennial allergy. AIM: To investigate perennial allergy compared with seasonal allergy as a risk factor for lower respiratory tract infections and exacerbations in asthma and whether this risk can be reduced by allergen immunotherapy (AIT). METHODOLOGY: This is a prospective register-based nationwide study of 18-44-year-olds treated with AIT during 1995-2014. Based on the type of AIT and use of anti-asthmatic drugs, patients were subdivided into two groups: perennial allergic asthma (PAA) versus seasonal allergic asthma (SAA). Data on antibiotics against lower respiratory tract infections (LRTI) and oral corticosteroids for exacerbations were analysed before starting AIT (baseline) and 3 years after completing AIT (follow-up). RESULTS: We identified 2688 patients with asthma treated with AIT, of whom 1249 had PAA and 1439 had SAA. At baseline, patients with SAA had more exacerbations (23.8% versus 16.5%, p≤0.001), but there were no differences in LRTI. During the 3-year follow-up, we observed a highly significant reduction of exacerbations with an average decrease of 57% in PAA and 74% in SAA. In addition, we observed a significant reduction of LRTI in both PAA and SAA: 17% and 20% decrease, respectively. CONCLUSION: AIT effectively reduced the risk of exacerbations and lower respiratory tract infections in both seasonal and perennial allergic asthma. Perennial allergy is seemingly not a stronger risk factor for respiratory infections and exacerbations than seasonal allergy.

Long-term prognosis following hospitalization for acute myocarditis - a matched nationwide cohort study.

OBJECTIVE: The aim of this study was to examine the long-term risk of heart failure (HF) and all-cause mortality, in patients discharged alive following hospitalization for myocarditis. Background. Prognosis in patients with apparently uncomplicated myocarditis is in general perceived as good, but data on long-term outcomes are sparse. Methods. From nationwide Danish registries we included patients without prior cardiac disease, discharged alive with a first-time diagnosis of myocarditis 1996-2016. Patients were matched 1:10 by age- and sex, with controls from the general population. Risk of HF hospitalization and death in cases and controls was compared by use of adjusted Cox regression analyses. Results. We identified 1557 patients with a first-time diagnosis of myocarditis, 72% men, median age 39 years. Patients with myocarditis had more hypertension, diabetes, and cancer, and received more pharmacotherapy prior to hospitalization compared to matched controls. During a mean follow-up of 8.5 years, the event rate of HF hospitalization was 8.7 vs. 2.2 per 1000 patient-years (py) in cases and controls; HR 4.59 (95% CI; 3.58-5.88) and for all-cause mortality, event rate 21.9 vs 11.2 per 1000 py; HR 2.10 (95% CI; 1.82-2.43). Among 784 patients with no events or HF medication one year after diagnosis, risk of HF hospitalization (HR 2.15; 95% CI; 1.18-3.92), and all-cause mortality (HR 1.62; 95% CI; 1.21-2.16) remained elevated compared to matched controls. Conclusion. Myocarditis in younger patients without prior cardiac disease was associated with a long-term excess risk of HF hospitalization, and death, even in patients free of events and HF medication 1 year after discharge.HighlightsMyocarditis ranges from chest discomfort to severe heart failure.In most patients, left ventricular ejection fraction recovers but the long-term adverse cardiac risk is unknown.Patients with myocarditis and no prior cardiac disease were at higher risk of death and heart failureRoutine follow-up may be warranted following an episode of acute myocarditis.

Risk Factors for Morbidity and Mortality Following Hospitalization for Pericarditis.

BACKGROUND: Viral or idiopathic pericarditis is a frequent condition, often considered benign, although prior studies have suggested that pericarditis is associated with both cardiovascular and noncardiovascular disease, for example, malignancy. OBJECTIVES: This study sought to assess mortality risk and morbidity patterns in patients with incident viral or idiopathic pericarditis. METHODS: In nationwide Danish registries, we identified patients discharged with a first-time diagnosis of pericarditis from 1996 to 2016. Patients with a severe underlying heart condition were excluded. The patients were matched 1:10 with individuals from the general population by sex and year of birth. We assessed 5-year mortality using Kaplan-Meier and Cox proportional hazards models adjusted for baseline comorbidities and identified subsequent hospital admissions. RESULTS: We identified 7,988 patients with pericarditis and 79,880 matched control individuals. The absolute 5-year survival probability was 92.9% and 95.8% in the pericarditis and control groups, respectively (adjusted hazard ratio: 1.31; 95% confidence interval: 1.13 to 1.52). The greatest difference in mortality was seen the first year, and it was primarily driven by the female part of the population. The incidence rate per 1,000 person-years of new-onset, admission-required diagnosis was higher in the pericarditis group both for cardiovascular and noncardiovascular diseases. CONCLUSIONS: We observed a higher mortality risk over 5 years in the pericarditis group, especially among the female patients, compared to matched control individuals. Furthermore, we observed a higher frequency of both cardiovascular and noncardiovascular hospital admissions, highlighting the need for focus on underlying morbidity in patients presenting with apparent viral or idiopathic pericarditis.

Proactive Prophylaxis With Azithromycin and HydroxyChloroquine in Hospitalised Patients With COVID-19 (ProPAC-COVID): A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The aim of this randomised GCP-controlled trial is to clarify whether combination therapy with the antibiotic azithromycin and hydroxychloroquine via anti-inflammation/immune modulation, antiviral efficacy and pre-emptive treatment of supra-infections can shorten hospitalisation duration for patients with COVID-19 (measured as "days alive and out of hospital" as the primary outcome), reduce the risk of non- invasive ventilation, treatment in the intensive care unit and death. TRIAL DESIGN: This is a multi-centre, randomised, Placebo-controlled, 2-arm ratio 1:1, parallel group double-blind study. PARTICIPANTS: 226 participants are recruited at the trial sites/hospitals, where the study will take place in Denmark: Aalborg, Bispebjerg, Gentofte, Herlev, Hillerød, Hvidovre, Odense and Slagelse hospitals. INCLUSION CRITERIA: • Patient admitted to Danish emergency departments, respiratory medicine departments or internal medicine departments • Age≥ 18 years • Hospitalized ≤48 hours • Positive COVID-19 test / diagnosis during the hospitalization (confirmed). • Men or non-fertile women. Fertile women* must not be pregnant, i.e. negative pregnancy test must be available at inclusion • Informed consent signed by the patient *Defined as after menarche and until postmenopausal (no menstruation for 12 months) Exclusion criteria: • At the time of recruitment, the patient uses >5 LO2/min (equivalent to 40% FiO2 if measured) • Known intolerance/allergy to azithromycin or hydroxychloroquine or hypersensitivity to quinine or 4-aminoquinoline derivatives • Neurogenic hearing loss • Psoriasis • Retinopathy • Maculopathy • Visual field changes • Breastfeeding • Severe liver diseases other than amoebiasis (INR> 1.5 spontaneously) • Severe gastrointestinal, neurological and hematological disorders (investigator-assessed) • eGFR <45 ml/min/1.73 m2 • Clinically significant cardiac conduction disorders/arrhythmias or prolonged QTc interval (QTc (f) of> 480/470 ms). • Myasthenia gravis • Treatment with digoxin* • Glucose-6-phosphate dehydrogenase deficiency • Porphyria • Hypoglycaemia (Blood glucose at any time since hospitalization of <3.0 mmol/L) • Severe mental illness which significantly impedes cooperation • Severe linguistic problems that significantly hinder cooperation • Treatment with ergot alkaloids *The patient must not be treated with digoxin for the duration of the intervention. For atrial fibrillation/flutter, select according to the Cardiovascular National Treatment Guide (NBV): Calcium antagonist, Beta blocker, direct current (DC) conversion or amiodarone. In case of urgent need for digoxin treatment (contraindication for the aforementioned equal alternatives), the test drug should be paused, and ECG should be taken daily. INTERVENTION AND COMPARATOR: Control group: The control group will receive the standard treatment + placebo for both types of intervention medication at all times. If part or all the intervention therapy being investigated becomes standard treatment during the study, this may also be offered to the control group. Intervention group: The patients in the intervention group will also receive standard care. Immediately after randomisation to the intervention group, the patient will begin treatment with: Azithromycin: Day 1-3: 500 mg x 1 Day 4-15: 250 mg x 1 If the patient is unable to take the medication orally by themselves, the medication will, if possible, be administered by either stomach-feeding tube, or alternatively, temporary be changed to clarithromycin 500 mg x 2 (this only in agreement with either study coordinator Pradeesh Sivapalan or principal investigator Jens-Ulrik Stæhr Jensen). This will also be done in the control group if necessary. The patient will switch back to azithromycin when possible. Hydroxychloroquine: Furthermore, the patient will be treated with hydroxychloroquine as follows: Day 1-15: 200 mg x 2 MAIN OUTCOMES: • Number of days alive and discharged from hospital within 14 days (summarises both whether the patient is alive and discharged from hospital) ("Days alive and out of hospital") RANDOMISATION: The sponsor (Chronic Obstructive Pulmonary Disease Trial Network, COP:TRIN) generates a randomisation sequence. Randomisation will be in blocks of unknown size and the final allocation will be via an encrypted website (REDCap). There will be stratification for age (>70 years vs. <=70 years), site of recruitment and whether the patient has any of the following chronic lung diseases: COPD, asthma, bronchiectasis, interstitial lung disease (Yes vs. No). BLINDING (MASKING): Participants and study personnel will both be blinded, i.e. neither will know which group the participant is allocated to. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): This study requires 226 patients randomised 1:1 with 113 in each group. TRIAL STATUS: Protocol version 1.8, from April 16, 2020. Recruitment is ongoing (first patient recruited April 6, 2020; final patient expected to be recruited October 31, 2020). TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04322396 (registered March 26, 2020) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Clinical presentation, management and prognosis of patients with cardiac sarcoidosis.

INTRODUCTION: The course and prognosis of cardiac sarcoidosis (CS) are sparsely described. The purpose of this study was to assess the clinical presentation, treatment response and prognosis for patients with CS. METHODS: This was a single-centre retrospective study of patients with CS from 2006 to 2016. A total of 197 patients with a sarcoidosis diagnosis were screened, and 17 patients (mean age 46.9 years, 59% men) were diagnosed with CS based on Japanese Ministry of Health and Welfare criteria; 53% were diagnosed by a positive MRI, 29% by endomyocardial biopsy. Of 17 patients, nine (53%) had a left ventricular ejection fraction (LVEF) < 45% at the time of diagnosis. The median follow-up was four years. In 13 patients, an implantable defibrillator was used and six of these (46%) received first appropriate shock therapy after a mean follow-up of two years. A total of 11 (65%) patients were treated with prednisolone and five (45%) of these 11 patients were also treated with another immunosuppressant. RESULTS: The median LVEF did not change at the last follow-up (p = 0.68), but improved in 30% of patients on combination therapy with prednisolone and proliferation inhibitors, whereas 23% of patients with prednisolone monotherapy experienced further worsening of LVEF. Immunosuppression was not used in 35% of patients. During follow-up, one patient underwent a successful heart transplant, one had a left ventricular assist device implantation and one died from septic shock. CONCLUSION: In CS patients, ventricular arrhythmias and impairment of LVEF were frequently seen, but the medium-term survival was excellent on heart failure therapy and immunosuppression. FUNDING: none. TRIAL REGISTRATION: Danish Data Protection Agency: (File no. RH-2016-301, I-Suite no. 04965).