First-in-man trial of ß3-adrenoceptor agonist treatment in chronic heart failure - impact on diastolic function.

Diastolic dysfunction (DD) in heart failure (HF) is associated with increased myocardial cytosolic calcium, and calcium-efflux via the sodium-calcium-exchanger depends on the sodium gradient. Beta-3-adrenoceptor (ß3-AR) agonists lower cytosolic sodium and have reversed organ congestion. Accordingly, ß3-AR agonists might improve diastolic function, which we aimed to assess. In a first-in-man, randomized, double-blinded trial, we assigned 70 patients with HF with reduced ejection fraction (HFrEF), NYHA II-III, and LVEF<40% to receive the ß3-AR agonist mirabegron (300 mg/day) or placebo for six months, in addition to recommended HF therapy. We performed echocardiography and cardiac computed tomography (CCT) and measured N-terminal pro-brain natriuretic peptide (NT-proBNP) at baseline and follow-up. DD was graded per multiple renowned algorithms. Baseline and follow-up data were available in 57 patients (59±11 years, 88% male, 49% ischemic heart disease). No clinically significant changes in diastolic measurements were found within or between groups by echocardiography (E/e' placebo: 13±7 to 13±5, p=0.21 vs mirabegron: 12±6 to 13±8, p=0.74, between group follow-up difference 0.2 [95% CI -3 to 4], p=0.89), or CCT (left atrial volume index: between group follow-up difference 9 ml/m2 [95% CI -3 to 19], p=0.15). DD gradings did not change within or between groups following two algorithms (p=0.72, p=0.75). NT-proBNP remained unchanged in both groups (p=0.74, p=0.64). In patients with HFrEF, no changes were identified in diastolic measurements, gradings or biomarker after ß3-AR stimulation compared to placebo. The findings add to previous literature questioning the role of impaired Na+-Ca2+ mediated calcium-export as a major culprit in DD. NCT01876433.

Incidence of infective endocarditis in patients considered at moderate risk.

AIMS: Stratification of patients at risk of infective endocarditis (IE) remains a cornerstone in guidance of prophylactic strategies of IE. However, little attention has been given to patients considered at moderate risk. METHODS AND RESULTS: Using Danish nationwide registries, we assessed the risk of IE in patients with aortic and mitral valve disorders, a cardiac implantable electronic device (CIED), or hypertrophic cardiomyopathy (HCM) and compared these patient groups with (i) controls from the background population using risk-set matching and (ii) a high-risk population (prosthetic heart valve). Cumulative incidence plots and multivariable adjusted Cox proportional hazard analysis were used to compare risk of IE between risk groups. We identified 83 453 patients with aortic or mitral valve disorder, 50 828 with a CIED, and 3620 with HCM. The cumulative risk of IE after 10 years was 0.9% in valve disorder, 1.3% in CIED, and 0.5% in HCM patients. Compared with the background population, valve disorder, CIED, and HCM carried a higher associated risk of IE, hazard ratio (HR) = 8.75 [95% confidence interval (CI) 6.36-12.02], HR = 6.63 (95% CI 4.41-9.96), and HR = 6.57 (95% CI 2.33-18.56), respectively. All three study groups were associated with a lower risk of IE compared with high-risk patients, HR = 0.27 (95% CI 0.23-0.32) for valve disorder, HR = 0.28 (95% CI 0.23-0.33) for CIED, and HR = 0.13 (95% CI 0.06-0.29) for HCM. CONCLUSIONS: Heart valve disorder, CIED, and patients with HCM were associated with a higher risk of IE compared with the background population but have a lower associated risk of IE compared with high-risk patients.

Prevalence of infective endocarditis in patients with positive blood cultures: a Danish nationwide study.

AIMS: Increasing attention has been given to the risk of infective endocarditis (IE) in patients with certain blood stream infections (BSIs). Previous studies have been conducted on selected patient cohorts, yet unselected data are sparse. We aimed to investigate the prevalence of IE in BSIs with bacteria typically associated with IE. METHODS AND RESULTS: By crosslinking nationwide registries from 2010 to 2017, we identified patients with BSIs typically associated with IE: Enterococcus faecalis (E. faecalis), Staphylococcus aureus (S. aureus), Streptococcus spp., and coagulase negative staphylococci (CoNS) and examined the concurrent IE prevalence. A trend test was used to examine temporal changes in the prevalence of IE. In total 69 021, distributed with 15 350, 16 726, 19 251, and 17 694 BSIs were identified in the periods of 2010-2011, 2012-2013, 2014-2015, and 2016-2017, respectively. Patients with E. faecalis had the highest prevalence of IE (16.7%) followed by S. aureus (10.1%), Streptococcus spp. (7.3%), and CoNS (1.6%). Throughout the study period, the prevalence of IE among patients with E. faecalis and Streptococcus spp. increased significantly (P = 0.0005 and P = 0.03, respectively). Male patients had a higher prevalence of IE for E. faecalis, Streptococcus spp., and CoNS compared with females. A significant increase in the prevalence of IE was seen for E. faecalis, Streptococcus spp., and CoNS with increasing age. CONCLUSION: For E. faecalis BSI, 1 in 6 had IE, for S. aureus BSI 1 in 10 had IE, and for Streptococcus spp. 1 in 14 had IE. Our results suggest that screening for IE seems reasonable in patients with E. faecalis BSI, S. aureus BSI, or Streptococcus spp. BSI.

Risk of stroke subsequent to infective endocarditis: A nationwide study.

BACKGROUND: The aim of the study was to investigate the associated risk of stroke after discharge of infective endocarditis (IE) in patients with stroke during IE admission compared with patients without stroke during IE admission. METHODS: Using Danish nationwide registries, we identified nonsurgically treated patients with IE discharged alive in the period from 1996 to 2016. The study population was grouped into (1) patients with stroke during IE admission and (2) patients without stroke during IE admission. Multivariable adjusted Cox proportional-hazard analysis was used to compare the associated risk of stroke between groups. RESULTS: We identified 4,284 patients with IE, of whom 239 (5.6%) had a stroke during IE admission. We identified differentials in the associated risk of stroke during follow-up between groups (P = .006 for interaction with time). The associated risk of stroke was higher in patients with stroke during IE admission with a 1-year follow-up, HR = 3.21 (95% CI 1.66-6.20), compared with patients without stroke during IE admission. From 1 to 5 years of follow-up, we identified no difference in the associated risk of stroke between groups, HR = 0.91 (95% CI 0.33-2.50). CONCLUSIONS: Patients with nonsurgically treated IE with a stroke during IE admission were at significant higher associated risk of subsequent stroke within the first year of follow-up as compared with patients without a stroke during IE admission. This risk difference was not evident beyond 1 year of discharge. These findings underline the need for identification of causes and mechanisms of recurrent strokes after IE to develop preventive means.

Incidence of infective endocarditis among patients considered at high risk.

Aims: Patients with prior infective endocarditis (IE), a prosthetic heart valve, or a cyanotic congenital heart disease (CHD) are considered to be at high risk of IE by guidelines. However, knowledge is sparse on the relative risk of IE between these three groups and compared controls. Methods and results: Using Danish nationwide registries (1996-2015), we identified all patients with prior IE, a prosthetic heart valve, or a complex CHD (defined as tetralogy of Fallot, truncus arteriosus, and transposition of great arteries) as well as matched control populations. Patients were followed up until death, end of study period, IE hospitalization, emigration, or a maximum of 10 years of follow-up, whichever came first. Multivariable adjusted Cox proportional hazard analysis was used to compare the risk of IE between the study groups and the matched controls. We included 25 945 patients: 5096 had prior IE, 19 478 had a prosthetic heart valve, and 1371 had complex CHD. The cumulative risk of IE at 10 years of follow-up was 8.8%, 6.0%, and 1.3% for patients with prior IE, a prosthetic valve, and complex CHD, respectively. Patients with prior IE and a prosthetic valve had a significant increased associated risk of IE compared with the matched controls [hazard ratio (HR) 65.4, 95% confidence interval (CI) 43.1-99.1 and HR 19.1, 95% CI 15.0-24.4), respectively]. No events occurred among the matched controls for the complex CHD group and an HR could not be calculated. Conclusion: All IE high-risk groups carried a higher risk of IE than the matched controls from the general population. These results justify the European and American guidelines in considering these groups at high risk of IE.

Incidence and factors associated with infective endocarditis in patients undergoing left-sided heart valve replacement.

Aims: Patients with left-sided heart valve replacement are considered at high-risk of infective endocarditis (IE). However, data on the incidence and risk factors associated with IE are sparse. Methods and results: Through Danish administrative registries, we identified patients who underwent left-sided heart valve replacement from January 1996 to December 2015. Patients were categorized in mitral and aortic valve replacement (MVR and AVR) and followed until: 12 years after valve surgery, end of study, death, emigration, or hospitalization due to IE, whichever came first. Multivariable adjusted Cox proportional hazard analysis was used to investigate which baseline characteristics were associated with IE. A total of 18 041 patients were included. The cumulative IE risk at 10 years follow-up was 5.2% in both MVR and AVR patients. In patients with MVR, male sex [hazard ratio (HR) = 1.68, 95% confidence interval (95% CI) 1.06-2.68], bioprosthetic valve (HR = 1.91, 95% CI 1.08-3.37), and heart failure (HR = 1.69, 95% CI 1.06-2.68) were among factors associated with an increased risk of IE. In AVR patients, male sex (HR = 1.59, 95% CI 1.33-1.89), bioprosthetic valve (HR = 1.70, 95% CI 1.35-2.15), and cardiac implantable electronic device (CIED) (HR = 1.57, 95% CI 1.19-2.06) were among factors associated with an increased risk of IE. Conclusion: Infective endocarditis after left-sided heart valve replacement is not uncommon and occurs in about 1/20 over 10 years. Male, bioprosthetic valve, and heart failure were among factors associated with IE in MVR patients while male, bioprosthetic valve, and CIED were among factors associated with IE in AVR patients.

Return to the workforce following infective endocarditis-A nationwide cohort study.

BACKGROUND: The ability to return to work after infective endocarditis (IE) holds important socioeconomic consequences for both patients and society, yet data on this issue are sparse. We examined return to the workforce and associated factors in IE patients of working age. METHODS: Using Danish nationwide registries, we identified 1,065 patients aged 18-60 years with a first-time diagnosis of IE (1996-2013) who were part of the workforce prior to admission and alive at discharge. RESULTS: One year after discharge, 765 (71.8%) patients had returned to the workforce, 130 (12.2%) were on paid sick leave, 76 (7.1%) received disability pension, 23 (2.2%) were on early retirement, 65 (6.1%) had died, and 6 (0.6%) had emigrated. Factors associated with return to the workforce were identified using multivariable logistic regression. Younger age (18-40 vs 56-60 years; odds ratio, 2.85; 95% CI, 1.71-4.76) and higher level of education (higher educational level vs basic school; 5.47, 2.05-14.6) and income (highest quartile vs lowest; 3.17, 1.85-5.46) were associated with return to the workforce. Longer length of hospital stay (>90 vs 14-30 days; 0.16, 0.07-0.38); stroke during IE admission (0.38, 0.21-0.71); and a history of chronic kidney disease (0.29, 0.11-0.75), chronic obstructive pulmonary disease (0.31, 0.13-0.71), and malignancy (0.39, 0.22-0.69) were associated with a lower likelihood of returning to the workforce. CONCLUSIONS: Seven of 10 patients who were part of the workforce prior to IE and alive at discharge were part of the workforce 1 year later. Younger age, higher socioeconomic status, and absence of major comorbidities were associated with return to the workforce.

Cardiac implantable electronic device and associated risk of infective endocarditis in patients undergoing aortic valve replacement.

Aims: Patients undergoing aortic valve replacement (AVR) are at increased risk of infective endocarditis (IE) as are patients with a cardiac implantable electronic device (CIED). However, few data exist on the IE risk after AVR surgery in patients with a CIED. Methods and results: Using the Danish administrative registries, we identified patients undergoing AVR from January 1996 to December 2015. Patients were categorized by CIED and non-CIED and followed up till hospitalization due to IE, death, 10 years after AVR discharge, end of study period (December 2015) or emigration, whichever came first. Using multivariable-adjusted Cox proportional hazard analysis with time-varying exposure, we investigated whether CIED was associated with an increased risk of IE. We included 15 538 patients (median age 71.4 years, 25th-75th percentiles 63.7-77.1, and 65.2% male). There were 890 patients with a CIED; 531 of these received their device during the AVR hospitalization and 14 648 patients with no CIED. The crude incidence rate of IE was 149.4/10 000 person-years in the CIED group and 74.3/10 000 person-years in the non-CIED group. Overall, CIED was associated with an increased risk of IE (hazard ratio 1.66, 95% confidence interval 1.27-2.17). There was no difference in associated IE according to the timing of CIED (P for interaction = 0.21 for CIED implantation before vs. in conjunction with AVR surgery). Conclusion: Patients with a CIED who underwent surgery for AVR were associated with an increased risk of IE compared with patients without a CIED. The association was independent of the timing of CIED implantation (before or in conjunction with AVR surgery).

Temporal changes in infective endocarditis guidelines during the last 12 years: High-level evidence needed.

BACKGROUND: Infective endocarditis (IE) is a complex disease necessitating extensive clinical guidelines. The guidelines from the American Heart Association (AHA) and the European Society of Cardiology (ESC) have been markedly extended during the last 12 years. We examined the evidence base for these changes. METHODS: IE guidelines published by AHA and ESC were reviewed. We categorized and combined guidelines into 3 time periods: (1) 2004 (AHA) and 2005 (ESC), (2) 2007 (AHA) and 2009 (ESC), and (3) 2015 (AHA) and 2015 (ESC). Number of recommendations, classes of recommendations (I, II, or III), and levels of evidence (LOE) (A, B, or C) were assessed and the changes over time. RESULTS: From period 1 to period 3, we found a statistically significant increase in total number of IE recommendations from 37 to 253 (P<.01), a 6.8-fold increase. There were a significant decrease in LOE A (from 7 [20.0%] in period 1 to 4 [1.6%] in period 3, P<.0001, a 57% decrease), a nonsignificant decrease in LOE B recommendations (from 17 [48.6%] in period 1 to 115 [45.9%] in period 3, P=.29, a 6.8-fold increase), and a significant increase in LOE C recommendations (from 11 [31.4%] in period 1 to 134 [53.0%] in period 3, P=.02, a 12.2-fold increase). CONCLUSIONS: The number of IE guideline recommendations has increased 6- to 7-fold during the last decade without a corresponding increase in evidence. These results highlight the strong need for more clinical studies to improve the level of evidence in IE guidelines.

Prehospital electrocardiographic acuteness score of ischemia is inversely associated with neurohormonal activation in STEMI patients with severe ischemia.

BACKGROUND: Elevated levels of N-terminal pro brain natriuretic peptide (NT-proBNP) are associated with adverse cardiovascular outcome after ST elevation myocardial infarction (STEMI). We hypothesized that decreasing acuteness-score (based on the electrocardiographic score by Anderson-Wilkins acuteness score of myocardial ischemia) is associated with increasing NT-proBNP levels and the impact of decreasing acuteness-score on NT-proBNP levels is substantial in STEMI patients with severe ischemia. METHODS: In 186 STEMI patients treated with primary percutaneous coronary intervention (pPCI), the severity of ischemia (according to Sclarovsky-Birnbaum severity grades of ischemia) and the acuteness-score were obtained from prehospital ECG. Patients were classified according to the presence of severe ischemia or non-severe ischemia and acute ischemia or non-acute ischemia. Plasma NT-proBNP (pmol/L) was obtained after pPCI within 24hours of admission and was correlated with the acuteness-score. RESULTS: NT-proBNP levels were median (25th-75th interquartile) 112 (51-219) pmol/L in patients with non-severe ischemia (71.5%) and 145 (79-339) in patients with severe ischemia (28.5%) (p=0.074). NT-proBNP levels were highest in patients with severe and non-acute ischemia compared to those with severe and acute ischemia (182 (98-339) pmol/L vs 105 (28-324) pmol/L, p=0.012). There was a negative correlation between acuteness-score and log(NT-proBNP) in patients with severe ischemia (r=0.395, p=0.003), which remained significant in multilinear regression analysis (ß=-0.155, p=0.007). No correlation was observed between the acuteness-score and log(NT-proBNP) in patients with non-severe ischemia (p=0.529) or in the entire population (p=0.187). CONCLUSION: In STEMI patients with severe ischemia, neurohormonal activation is inversely associated with ECG patterns of acute myocardial ischemia.

Early diastolic strain rate in relation to systolic and diastolic function and prognosis in acute myocardial infarction: a two-dimensional speckle-tracking study.

AIMS: Diastolic dysfunction in acute myocardial infarction (MI) is associated with adverse outcome. Recently, the ratio of early mitral inflow velocity (E) to global diastolic strain rate (e'sr) has been proposed as a marker of elevated LV filling pressure. However, the prognostic value of this measure has not been demonstrated in a large-scale setting when existing parameters of diastolic function are known. We hypothesized that the E/e'sr ratio would be independently associated with an adverse outcome in patients with MI. METHODS AND RESULTS: We prospectively included patients with MI and performed echocardiography with comprehensive diastolic evaluation including E/e'sr. The relationship between E/e'sr and the primary composite endpoint (all-cause mortality, hospitalization for heart failure (HF), stroke, and new onset atrial fibrillation) was analysed with Cox models. A total of 1048 patients (mean age 63 ± 12, 73% male) were included and 142 patients (13.5%) reached the primary endpoint (median follow-up 29 months). A significant prognostic value was found for E/e'sr [hazard ratio (HR) per 1 unit change: 2.36, 95% confidence interval (CI): 2.02-2.75, P < 0.0001]. After multivariable adjustment E/e'sr remained independently related to the combined endpoint (HR per 1 unit change, 1.50; CI: 1.05-2.13, P = 0.02). The prognostic value of E/e'sr was driven by mortality (HR per 1 unit change, 2.52; CI: 2.09-3.04, P < 0.0001) and HF admissions (HR per 1 unit change, 2.79; CI: 2.23-3.48, P < 0.0001). CONCLUSION: Deformation-based E/e'sr contributes important information about global myocardial relaxation superior to velocity-based analysis and is independently associated with the outcome in acute MI.

The association between renal impairment and cardiac structure and function in patients with acute myocardial infarction.

BACKGROUND: Renal dysfunction in patients with acute myocardial infarction (MI) is an important predictor of short- and long-term outcome. Cardiac abnormalities dominated by left ventricular (LV) hypertrophy are common in patients with chronic renal dysfunction. However, limited data exists on the association between LV systolic- and diastolic function assessed by comprehensive echocardiography and renal dysfunction in contemporary unselected patients with acute MI. METHODS: We prospectively included 1054 patients with acute MI (mean age 63 years, 73% male) and performed echocardiographic assessment of systolic and diastolic function within 48 hours of admission as well as estimated glomerular filtration rate (eGFR). RESULTS: Reduced eGFR was significantly associated with LV mass, LV ejection fraction, LV global strain (GLS) and E/e' ratio. After multivariable adjustment, E/e' ratio (P = .0096) remained the only echocardiographic measure independently associated with decreasing eGFR. During follow-up a total of 113 patients (10.7%) patients experienced the composite endpoint of all-cause mortality or hospitalization for heart failure. An eGFR <60 mL/min per 1.73 m(2) was significantly associated with outcome (HR, 1.71; 95% CI, 1.12-2.62; P = .0131) after adjustment for age, diabetes, hypertension, Killip class >1, multivessel disease and troponin. The prognostic impact of an eGFR <60 mL/min per 1.73 m(2) was only modestly altered by addition of LV mass or E/e' ratio whereas addition of LV ejection fraction or GLS attenuated its importance considerably. CONCLUSION: Renal dysfunction in patients with acute MI is independently associated with echocardiographic evidence of increased LV filling pressure. However, the prognostic importance of renal dysfunction is attenuated to a greater degree by LV longitudinal systolic function.

Development and validation of the ASGARD risk score for safe monitoring in asymptomatic nonsevere aortic stenosis.

AIMS: Current guidelines recommend serial echocardiography at minimum 1-2 year intervals for monitoring patients with nonsevere aortic valve stenosis (AS), which is costly and often clinically inconsequential.We aimed to develop and test whether the biomarker-based ASGARD risk score (Aortic Valve Stenosis Guarded by Amplified Risk Determination) can guide the timing of echocardiograms in asymptomatic patients with nonsevere AS. METHODS: The development cohort comprised 1,093 of 1,589 (69%) asymptomatic patients with mild-to-moderate AS who remained event-free one year after inclusion into the SEAS trial. Cox regression landmark analyses with a 2-year follow-up identified the model (ASGARD) with the lowest Akaike information criterion for association to AS-related composite outcome (heart failure hospitalization, aortic valve replacement, or cardiovascular death). Fine-Gray analyses provided cumulative event rates by ASGARD score quartiles. The ASGARD score was internally validated in the remaining 496 patients (31%) from the SEAS-cohort and externally in 71 asymptomatic outpatients with nonsevere AS from six Copenhagen hospitals. RESULTS: The ASGARD score comprises updated measurements of heart rate and age- and sex-adjusted N-terminal pro-brain natriuretic peptide upon transaortic maximal velocity (Vmax) from the previous year. The ASGARD score had high predictive accuracy across all cohorts (external validation: area under the curve: 0.74 [95% CI, 0.62-0.86]), and similar to an updated Vmax measurement. An ASGARD score ≤50% was associated with AS-related event rates ≤5% for a minimum of 15 months. CONCLUSION: The ASGARD score could provide a personalized and safe surveillance alternative to routinely planned echocardiograms, so physicians can prioritize echocardiograms for high-risk patients.

In this study, we developed and examined the potential of the novel ASGARD risk score to tailor personalized follow-up intervals for diagnostic heart scans, incorporating updated heart rate and blood marker measurements along with the heart scan data from the previous year. Patients with the ASGARD risk score within the lowest 50% had a low annual risk of aortic valve-related events (less than 5%) for a minimum of 15 months.In clinical settings, the ASGARD score could provide a personalized and safe monitoring alternative to routine heart scans, prioritizing the diagnostic heart scans for high-risk patients.

Simple regional strain pattern analysis to predict response to cardiac resynchronization therapy: rationale, initial results, and advantages.

BACKGROUND: A classical strain pattern of early contraction in one wall and prestretching of the opposing wall followed by late contraction has previously been associated with left bundle branch block (LBBB) activation and short-term response to cardiac resynchronization therapy (CRT). Aims of this study were to establish the long-term predictive value of an LBBB-related strain pattern and to identify changes in contraction patterns during short-term and long-term CRT. METHODS AND RESULTS: Sixty-seven patients with standard CRT criteria were prospectively enrolled between early 2009 and late 2010. Echocardiography including regional strain analysis by 2-dimensional speckle tracking was performed 1 week before implantation, at day 1, and 6 months after. Response was defined as a decrease in left ventricular end-systolic volume ≥ 15%. The predictive ability of a classical pattern was compared with time-to-peak measurements from velocity and deformation analysis. Forty-three patients (65%) were classified as responders. The presence of a classical pattern showed 91% specificity and 95% sensitivity for response and performed significantly better than time-to-peak parameters in prediction of response to CRT (P < .001, all). In responders, CRT acutely increased septal longitudinal peak systolic strain (-8.7% ± 3.6% to -11.1% ± 3%, P < .001) but not in nonresponders. CONCLUSIONS: The classical pattern is highly predictive of response to CRT and superior to time-to-peak methods. Patients who obtain long-term reverse remodeling are characterized by short-term reversal of the classical strain pattern. These findings emphasize the value of recognizing potentially reversible strain patterns in selection of CRT candidates.

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.

Plasma sodium and mortality risk in patients with myocardial infarction and a low LVEF.

BACKGROUND: Hyponatremia is a known prognostic factor for mortality in patients with heart failure but has not been extensively studied in patients with myocardial infarction (MI). This study was, therefore, designed to evaluate whether plasma sodium and hyponatremia (< 135 mM) are associated with mortality risk in patients with MI. MATERIALS AND METHODS: In retrospective analyses using data from the Trandolapril Cardiac Evaluation (TRACE) study--a randomized, double-blind, placebo-controlled trial of trandolapril in 1749 patients with MI and left ventricular ejection fraction (LVEF) ≤ 35%--associations between plasma sodium or hyponatremia and more than 15-year mortality risk were evaluated in multivariate Cox proportional hazard models including traditional clinical confounders before and after additional adjustment for renal function, use of diuretics or both. RESULTS: During the extended follow-up time, 1462 patients died. Both hyponatremia [Hazard ratio: 1·30 (95% CI: 1·13-1·50), P < 0·001] and plasma sodium [Hazard Ratio(pro mM increase in P-Na): 0·98 (95% CI: 0·96-0·99), P = 0·004] were associated with mortality risk, and the adjusted parameter estimates were not affected by additional adjustment for renal function, use of diuretics or both. CONCLUSIONS: Hyponatremia and plasma concentrations of sodium are associated with long-term mortality risk in patients with MI complicated by left ventricular systolic dysfunction. Importantly, these associations are independent of renal function and use of diuretics. Whether the associations between plasma sodium or hyponatremia and long-term mortality risk reflect a causation or merely the severity of the underlying cardiac disease remains to be clarified.

Valve regurgitation in patients surviving endocarditis and the subsequent risk of heart failure.

BACKGROUND: Significant valve regurgitation is common in patients surviving native valve infective endocarditis (IE), however the associated risk of heart failure (HF) subsequent to hospital discharge after IE is sparsely described. METHODS: We linked data from the East Danish Endocarditis Registry with administrative registries from 2002 to 2016 and included patients treated medically for IE who were discharged alive. Left-sided valve regurgitation was assessed by echocardiography at IE discharge and examined for longitudinal risk of HF. Multivariable adjusted Cox analysis was used to assess the associated risk of HF in patients with regurgitation (moderate or severe) compared with patients without regurgitation. RESULTS: We included 192 patients, 87 patients with regurgitation at discharge (30 with aortic regurgitation and 57 with mitral regurgitation) and 105 patients without. The cumulative risk of HF at 5 years of follow-up was 28.7% in patients with regurgitation at IE discharge and 12.4% in patients without regurgitation; the corresponding multivariable adjusted HR was 3.53 (95% CI 1.72 to 7.25). We identified an increased associated risk of HF for patients with aortic regurgitation (HR=2.91, 95% CI 1.14 to 7.43) and mitral regurgitation (HR=3.95, 95% CI 1.80 to 8.67) compared with patients without regurgitation. During follow-up, 21.9% and 5.7% underwent left-sided valve surgery among patients with and without regurgitation. CONCLUSION: In patients surviving IE, treated medically, we observed that severe or moderate left-sided native valve regurgitation was associated with a significantly higher risk of HF compared with patients without regurgitation at IE discharge. Close monitoring of these patients is needed to initiate surgery timely.

Echocardiographic subtypes of heart failure in consecutive hospitalised patients with dyspnoea.

Heart failure with preserved ejection fraction (HFpEF) involves half of hospitalised patients with heart failure (HF), but estimates vary due to unclear diagnostic criteria. We performed a prospective observational study of hospitalised patients admitted with dyspnoea. The aim was to apply contemporary guidelines to diagnose HF due to valvular disease (HFvhd), HF due to reduced ejection fraction (HFrEF), HF due to midrange EF (HFmrEF) and HFpEF in relation to presumed cardiac or non-cardiac dyspnoea. Methods: We included consecutive hospitalised patients with presumed HF or dyspnoea and excluded patients with acute coronary syndrome, estimated glomerular filtration rate <30 mL/min/1.73 m² or low NT-proBNP (<296 ng/L). Higher age-adjusted NT-proBNP values excluded patients with presumptive non-cardiac dyspnoea. Contemporary criteria for HFpEF and diastolic dysfunction were assessed, and we adjudicated whether acute decompensated HF (ADHF) had been the primary diagnosis. Results: Of 707 eligible patients, we included 370 patients of whom 75 had non-cardiac dyspnoea. Of these, 10% (38/370) had no cardiac dysfunction. Cardiac dysfunction consisted of 18.4%, HFvhd, 30.1% HFrEF, 10.2% HFmrEF and 41.3% HFpEF. HFpEF was twice as common in presumptive non-cardiac dyspnoea versus cardiac dyspnoea (71% vs 34%, p<0.0001). However, adjudicated ADHF was the primary diagnosis in 80% of HFrEF, 62% of HFmrEF and just 28% of HFpEF. Conclusion: HF according to contemporary criteria applied to 90% of patients admitted with dyspnoea and elevated NT-proBNP irrespective of the presumptive cause of dyspnoea, of whom 10% had HFmrEF and 41% HFpEF. However, significant non-cardiac diagnoses related to 9 out of 10 with HFpEF with pulmonary disease as the predominant adjudicated problem.

Residual vegetation after treatment for left-sided infective endocarditis and subsequent risk of stroke and recurrence of endocarditis.

BACKGROUND: Little is known about the subsequent risk of stroke and recurrence of IE for patients surviving infective endocarditis (IE) with a residual vegetation at discharge. METHODS: Patients were consecutively included in the East Danish Endocarditis Registry from 2002 to 2012. We included patients undergoing medical treatment only during IE admission who were discharged alive. Size of residual vegetation was assessed by echocardiography at discharge and patients were categorized according to median length of residual vegetation. Using multivariable adjusted Cox Proportional hazard analysis, we assessed the associated risk of stroke and recurrence of IE between study groups. RESULTS: Among 915 IE patients, 305 were included after selection criteria were applied, 151 patients without residual vegetation, 73 patients with 1-5 mm residual vegetation, and 81 patients with >5 mm residual vegetation. We identified an increased associated risk of stroke for patients with 1-5 mm and > 5 mm residual vegetation, HR = 0.88 (95% CI: 0.26-2.94) and HR = 2.95 (95% CI:1.18-7.34) compared with patients without residual vegetation. No difference was seen between groups for the associated risk of recurrence of IE, HR = 1.39 (95% CI: 0.91-2.13) and HR = 1.38 (95% CI: 0.91-2.10) for patients with a residual vegetation 1-5 mm and > 5 mm compared with patients without residual vegetation. CONCLUSIONS: Patients surviving IE with a residual vegetation > 5 mm had an increased associated risk of stroke compared with patients without residual vegetation. These findings provide new perspectives on a patient group sparsely describe, suggesting a potential benefit of therapy among patients surviving IE with a residual vegetation > 5 mm.

Prevalence of Infective Endocarditis in Enterococcus faecalis Bacteremia.

BACKGROUND: Enterococcus faecalis is the third most frequent cause of infective endocarditis (IE). Despite this, no systematic prospective echocardiography studies have examined the prevalence of IE in patients with E. faecalis bacteremia. OBJECTIVES: This study sought to determine the prevalence of IE in patients with E. faecalis bacteremia. The secondary objective was to identify predictors of IE. METHODS: From January 1, 2014, to December 31, 2016, a prospective multicenter study was conducted with echocardiography in consecutive patients with E. faecalis bacteremia. Predictors of IE were assessed using multivariate logistic regression with backward elimination. RESULTS: A total of 344 patients with E. faecalis bacteremia were included, all examined using echocardiography, including transesophageal echocardiography in 74% of the cases. The patients had a mean age of 74.2 years, and 73.5% were men. Definite endocarditis was diagnosed in 90 patients, resulting in a prevalence of 26.1 ± 4.6% (95% confidence interval [CI]). Risk factors for IE were prosthetic heart valve (odds ratio [OR]: 3.93; 95% CI: 1.76 to 8.77; p = 0.001), community acquisition (OR: 3.35; 95% CI: 1.74 to 6.46; p < 0.001), ≥3 positive blood culture bottles (OR: 3.69; 95% CI: 1.88 to 7.23; p < 0.001), unknown portal of entry (OR: 2.36; 95% CI: 1.26 to 4.40; p = 0.007), monomicrobial bacteremia (OR: 2.73; 95% CI: 1.23 to 6.05; p = 0.013), and immunosuppression (OR: 2.82; 95% CI: 1.20 to 6.58; p = 0.017). CONCLUSIONS: This study revealed a high prevalence of 26% definite IE in patients with E. faecalis bacteremia, suggesting that echocardiography should be considered in all patients with E. faecalis bacteremia.