Immune Response and Risk of Decompensation following SARS-CoV-2 Infection in Outpatients with Advanced Chronic Liver Disease.

Advanced chronic liver disease (ACLD) is associated with a wide spectrum of immune dysfunction. The clinical impact of SARS-CoV-2 on the development of decompensation and immune response in unvaccinated outpatients has not as yet been clearly defined. This study aimed to evaluate the clinical and immunological impact of SARS-CoV-2 on outpatients with ACLD. This is an observational case-control study, in which ACLD outpatients were included prospectively and consecutively and classified into two groups: SARS-CoV-2 infected and non-infected. Patients' baseline characteristics and infection data were collected and analyzed. Immunoglobulin G (IgG) levels against Spike 1 were evaluated. The primary endpoint was risk of liver decompensation during follow-up, assessed after propensity score matching and adjusted by Cox regression. Between October 2020 and July 2021, ACLD outpatients (n = 580) were identified, and 174 patients with clinical follow-up were included. SARS-CoV-2 infection incidence was 7.6% (n = 44). Risk of liver decompensation was significantly higher after infection (HR = 2.43 [1.01-5.86], p = 0.048) vs. non-infection. The time of IgG evaluation was similar in all patients (n = 74); IgG concentrations were significantly higher in compensated vs. decompensated patients (1.02 ± 0.35 pg/mL vs. 0.34 ± 0.16 pg/mL, p < 0.0001) and correlated with hemoglobin levels. The dysregulation of the innate immune response in patients with decompensated liver disease increased the risk of further decompensation following SARS-CoV-2, mainly due to a worsening of ascites.

Home Blood Pressure Self-monitoring plus Self-titration of Antihypertensive Medication for Poorly Controlled Hypertension in Primary Care: the ADAMPA Randomized Clinical Trial.

BACKGROUND: Patient empowerment through pharmacological self-management is a common strategy in some chronic diseases such as diabetes, but it is rarely used for controlling blood pressure. OBJECTIVE: This study aimed to assess self-monitoring plus self-titration of antihypertensive medication versus usual care for reducing systolic blood pressure (SBP) at 12 months in poorly controlled hypertensive patients. DESIGN: The ADAMPA study was a pragmatic, controlled, randomized, non-masked clinical trial with two parallel arms in Valencia, Spain. PARTICIPANTS: Hypertensive patients older than 40 years, with SBP over 145 mmHg and/or diastolic blood pressure (DBP) over 90 mmHg, were recruited from July 2017 to June 2018. INTERVENTION: Participants were randomized 1:1 to usual care versus an individualized, pre-arranged plan based on self-monitoring plus self-titration. MAIN MEASURE: The primary outcome was the adjusted mean difference (AMD) in SBP between groups at 12 months. KEY RESULTS: Primary outcome data were available for 312 patients (intervention n=156, control n=156) of the 366 who were initially recruited. The AMD in SBP at 12 months (main analysis) was -2.9 mmHg (95% CI, -5.9 to 0.1, p=0.061), while the AMD in DBP was -1.9 mmHg (95% CI, -3.7 to 0.0, p=0.052). The results of the subgroup analysis were consistent with these for the main outcome measures. More patients in the intervention group achieved good blood pressure control (<140/90 mmHg) at 12 months than in the control group (55.8% vs 42.3%, difference 13.5%, 95% CI, 2.5 to 24.5%, p=0.017). At 12 months, no differences were observed in behavior, quality of life, use of health services, or adverse events. CONCLUSION: Self-monitoring plus self-titration of antihypertensive medication based on an individualized pre-arranged plan used in primary care may be a promising strategy for reducing blood pressure at 12 months compared to usual care, without increasing healthcare utilization or adverse events. TRIAL REGISTRATION: EudraCT, number 2016-003986-25 (registered 17 March 2017) and clinicaltrials.gov , NCT03242785.

Plasma circular RNA hsa_circ_0001445 and coronary artery disease: Performance as a biomarker.

The role of circular RNAs (circRNAs) as biomarkers remains poorly characterized. Here, we investigated the performance of the circRNA hsa_circ_0001445 as a biomarker of coronary artery disease (CAD) in a real-world clinical practice setting. Plasma hsa_circ_0001445 was measured in a study population of 200 consecutive patients with suspected stable CAD who had undergone coronary computed tomographic angiography (CTA). Multivariable logistic models were constructed combining conventional risk factors with established biomarkers and hsa_circ_0001445. Model robustness was internally validated by the bootstrap technique. Biomarker accuracy was evaluated using the C-index. The integrated discrimination improvement (IDI) and net reclassification improvement (NRI) were also calculated. Risk groups were developed via classification tree models. The stability of plasma hsa_circ_0001445 was evaluated under different clinical conditions. hsa_circ_0001445 levels were associated with higher coronary atherosclerosis extent and severity with a 2-fold increase across tertiles (28.4%-50.0%). Levels of hsa_circ_0001445 were proportional to coronary atherosclerotic burden, even after comprehensive adjustment for cardiovascular risk factors, medications, and established biomarkers (fully adjusted OR = 0.432 for hsa_circ_0001445 as a continuous variable and fully adjusted OR = 0.277 for hsa_circ_0001445 as a binary variable). The classification of patients was improved with the incorporation of hsa_circ_0001445 into a base clinical model (CM) composed of conventional cardiovascular risk factors, showing an IDI of 0.047 and NRI of 0.482 for hsa_circ_0001445 as a continuous variable and an IDI of 0.056 and NRI of 0.373 for hsa_circ_0001445 as a binary variable. A trend toward higher discrimination capacity was also observed (C-indexCM  = 0.833, C-indexCM+continuous hsa_circ_0001445  = 0.856 and C-indexCM+binary hsa_circ_0001445  = 0.855). Detailed analysis of stability showed that hsa_circ_0001445 was present in plasma in a remarkably stable form. In vitro, hsa_circ_0001445 was downregulated in extracellular vesicles secreted by human coronary smooth muscle cells upon exposure to atherogenic conditions. In patients with suspected stable CAD referred for coronary CTA, plasma hsa_circ_0001445 improves the identification of coronary artery atherosclerosis.

Frailty in outpatients with cirrhosis: A prospective observational study.

BACKGROUND AND AIM: Frailty is increasingly recognized as a major prognostic factor in cirrhosis in addition to conventional liver insufficiency scores. The aim was to compare the prevalence and characteristics of frailty between patients with cirrhosis and controls, and to analyse its prognostic value. METHODS: We included outpatients with cirrhosis and age- and gender-matched non-cirrhotic controls. Frailty was defined according to the Fried frailty criteria. In patients with cirrhosis, we analysed the ability of the degree of frailty to predict a composite endpoint, consisting of hospitalization, admission to a long-term care centre, falls or death. RESULTS: We included 135 patients with cirrhosis and 135 controls. The prevalence of frailty was higher among patients with cirrhosis: 35 (25.9%) frail, 74 (54.8%) pre-frail and 26 (19.2%) robust vs 14 (10.4%) frail, 67 (49.6%) pre-frail and 54 (40%) robust (P < .001) in controls. This difference was mainly as a result of decreased muscle strength in patients with cirrhosis. During follow-up, frail patients with cirrhosis showed a higher probability of composite endpoint, hospitalization and falls than pre-frail and robust cirrhotic patients but mortality was similar. MELD-Na score and frailty were independent predictive factors for hospitalization, frailty for falls, and MELD-Na score and albumin for survival. Vitamin D deficiency and increased cystatin C were associated with frailty. CONCLUSIONS: Frailty was more frequent in outpatients with cirrhosis than in controls, mainly because of a decrease in muscle strength, and it could be a predictive factor for hospitalization and falls in these patients.

Multimorbidity and medication complexity: New challenges in heart transplantation.

INTRODUCTION: Multimorbidity and therapeutic complexity are a recognized problem in the heart transplant (HTx) population. However, little is known about how best to quantify this complexity or the strategies that could reduce its burden. METHODS: This single-center, observational study included adult heart transplant recipients (HTxR) >1.5 years from transplant. We assessed multimorbidity (>2 comorbidities) and the patient-level Medication Regimen Complexity Index Spanish version (pMRCI-S) score. We also analyzed the independent predictors of pMRCI-S and the impact of the index score on specific clinical variables. RESULTS: We included 135 chronic-stage HTxR. Comorbidities significantly increased after HTx (6 ± 3 vs 2 ± 2, P-value < .001). Patients took 12 ± 3 chronic drugs/d, 58% of them to treat comorbidities. The mean total pMRCI-S score was 42 ± 11, higher than in several other chronic diseases. The medication category drugs to treat comorbidities predicted a higher total pMRCI-S score (OR = 3.12, 95% CI 2.8-3.43, P-value < .001). Therapeutic complexity after HTx had an impact on solid malignancies (OR = 1.1, 95% CI 1.02-1.18, P-value = .02) and renal function (OR=-0.81, 95% CI -1.21-(-0.42), P-value < .001). CONCLUSIONS: The multimorbidity and pMRCI-S scores obtained in HTx population were worrisomely high. The pMRCI score is a sensitive method that allows identification of the factors determining therapeutic complexity after HTx and selection of strategies to reduce pMRCI-S values.

Patient-Associated Predictors of 15- and 30-Day Readmission After Hospitalization for Acute Heart Failure.

BACKGROUND: Identifying readmission predictors in heart failure (HF) patients may help guide preventative efforts and save costs. We aimed to identify 15- and 30-day readmission predictors due to cardiovascular reasons. METHODS AND RESULTS: A total of 1831 patients with acute HF admission were prospectively followed during a year. Patient-associated variables were gathered at admission/discharge and events during follow-up. A multivariate Fine and Gray competing risk regression model and a cumulative incidence function were used to identify predictors and build a risk score model for 15- and 30-day readmission. The 15- and 30-day readmission rates due to cardiovascular reasons were 7.1% and 13.9%. Previous acute myocardial infarction, congestive signs at discharge, and length of stay > 9 days were predictors of 15- and 30-day readmission, while much weight loss and large NT-ProBNP reduction were protective factors. The NT-ProBNP reduction was larger at 30 days (> 55%) vs 15 days (> 40%) to protect from readmission. Glomerular filtration rate at discharge < 60 mL/min/1.73m2 and > 1 previous admissions due to HF were predictors of 30-day readmission, while first post-discharge control at an HF unit was a protective factor. CONCLUSIONS: Previous identified factors for early readmission were confirmed. The NT-ProBNP reduction should be increased (> 55%) to protect from 30-day readmission.

Electrophysiological Effects of Selective Atrial Coronary Artery Occlusion in Humans.

BACKGROUND: The arrhythmogenesis of ventricular myocardial ischemia has been extensively studied, but models of atrial ischemia in humans are lacking. This study aimed at describing the electrophysiological alterations induced by acute atrial ischemia secondary to atrial coronary branch occlusion during elective coronary angioplasty. METHODS AND RESULTS: Clinical data, 12-lead ECG, 12-hour Holter recordings, coronary angiography, and serial plasma levels of high-sensitivity troponin T and midregional proatrial natriuretic peptide were prospectively analyzed in 109 patients undergoing elective angioplasty of right or circumflex coronary arteries. Atrial coronary branches were identified and after the procedure patients were allocated into two groups: atrial branch occlusion (ABO, n=17) and atrial branch patency (non-ABO, n=92). In comparison with the non-ABO, patients with ABO showed: (1) higher incidence of periprocedural myocardial infarction (20% versus 53%, P=0.01); (2) more frequent intra-atrial conduction delay (19% versus 46%, P=0.03); (3) more marked PR segment deviation in the Holter recordings; and (4) higher incidence of atrial tachycardia (15% versus 41%, P=0.02) and atrial fibrillation (0% versus 12%, P=0.03). After adjustment by a propensity score, ABO was an independent predictor of periprocedural infarction (odds ratio, 3.4; 95% confidence interval, 1.01-11.6, P<0.05) and atrial arrhythmias (odds ratio, 5.1; 95% confidence interval, 1.2-20.5, P=0.02). CONCLUSIONS: Selective atrial coronary artery occlusion during elective percutaneous transluminal coronary angioplasty is associated with myocardial ischemic damage, atrial arrhythmias, and intra-atrial conduction delay. Our data suggest that atrial ischemic episodes might be considered as a potential cause of atrial fibrillation in patients with chronic coronary artery disease.

Impact of Pulmonary Artery Catheter Use on Short- and Long-Term Mortality in Patients with Cardiogenic Shock.

OBJECTIVES: The impact of pulmonary artery catheterization (PAC) on survival in patients with cardiogenic shock (CS) is not well established. This study aimed to assess whether Swan-Ganz catheter monitoring is related to short- and long-term mortality in patients with CS. METHODS: One hundred and twenty-nine consecutive patients with a first admission for CS were prospectively enrolled in a single-center registry between December 2005 and May 2009, and were subsequently followed up over 5.3 years. RESULTS: PAC was used in 64% of all patients with a mean age of 68 years (65% men). After adjustment for age, gender and the presence of CS upon admission, PAC was associated with lower short-term mortality [hazard ratio (HR) = 0.55, 95% confidence interval (CI) 0.35-0.86, p = 0.008] as well as lower mortality rates in the long-term follow-up (HR = 0.63, 95% CI 0.41-0.97, p = 0.035). In a subgroup analysis, the use of PAC was associated with reduced mortality in patients without acute coronary syndrome (ACS), i.e. 49% in the Swan-Ganz group vs. 82% (p = 0.010), but there was no difference within the ACS group. CONCLUSIONS: The use of PAC in patients with CS was associated with lower short- and long-term mortality rates after adjustment for age, gender and the presence of shock upon admission. This benefit was only significant in those patients without ACS.

Home exercise, branched-chain amino acids, and probiotics improve frailty in cirrhosis: A randomized clinical trial.

BACKGROUND: Frailty is a predictive factor of hospitalization, falls, and mortality in patients with cirrhosis, regardless of the degree of liver failure. The aim was to analyze whether a multifactorial intervention consisting of home-based exercise, branched-chain amino acids, and a multistrain probiotic can improve frailty in these patients. METHODS: Outpatients with cirrhosis were classified according to the Liver Frailty Index (LFI). Prefrail and frail patients were randomized into 2 groups. The intervention group was assigned to a multifactorial intervention consisting of exercise at home, branched-chain amino acid supplements, and a multistrain probiotic for 12 months. The control group received standard care. All patients were prospectively followed up every 3 months for 1 year to determine LFI, incidence of falls, emergency room visits, hospitalizations, and mortality. RESULTS: Thirty-two patients were included: 17 patients were assigned to the intervention group and 15 to the control group. In the intervention group, the baseline LFI decreased at 3, 6, 9, and 12 months (p = 0.019 for overall change with respect to the control group). The change in LFI (ΔLFI) at 12 months was -0.71 ± 0.24 in the intervention group and -0.09 ± 0.32 in the control group (p<0.001). During follow-up, patients in the intervention group had a lower 1-year probability of falls (6% vs. 47%, p = 0.03) and emergency room visits (10% vs. 44%, p = 0.04) than patients in the control group. CONCLUSIONS: A long-term multifactorial intervention that included exercise at home, branched-chain amino acids, and a multistrain probiotic improved frailty in outpatients with cirrhosis and was associated with a decrease in the incidence of clinical events such as falls and emergency room visits.

Binge drinking at time of bariatric surgery is associated with liver disease, suicides, and increases long-term mortality.

BACKGROUND AND AIMS: Alcohol use disorder has been reported in patients undergoing bariatric procedures, but the pattern of alcohol consumption has not been evaluated. We investigated the prevalence, risk factors, and impact of binge drinking (BD) at the time of surgery and during follow-up. METHODS: A prospective, longitudinal study of subjects undergoing bariatric surgery was included in the LABS-2 registry between 2006 and 2009. Participants with AUDIT questionnaire at the time of surgery and a minimum of 12 months follow-up were included. BD was defined as consuming ≥5 drinks on at least 1 occasion in the previous month. Liver biopsies were obtained during bariatric procedures in not all cases. Survival analysis was performed with the adjusted Cox regression model and competing risk. RESULTS: A total of 2257 subjects were included, with a median follow-up of 79 months. The prevalence of BD at time of surgery was 12%, and it raised up to 23% during follow-up. Patients with BD predominantly had a binge eating disorder (OR=1.35 [95% CI: 1.04-1.76]), regularly consumed fast food [OR=1.4 (95% CI: 1.07-1.85)] and used other drugs (OR=2.65 [95% CI: 1.74-4.04]). Within liver biopsies evaluation, BD showed higher hepatic iron deposits (OR=3.00 [95% CI: 1.25-7.21]). BD at the time of surgery was associated with a higher risk of BD during follow-up (OR=10.49 [95% CI: 7.86-14.00]) and long-term mortality (HR: 3.21 [95% CI: 1.67-6.18]). Specific causes of death in these patients with BD were liver disease (p=0.020), suicide (p=0.015), neoplasms (p=0.034), and respiratory (p=0.025). CONCLUSIONS: The prevalence of BD in patients undergoing bariatric surgery is high and increases the risk of postoperative liver disease, suicides, and long-term mortality.

Association of Vitamin K and Non-Vitamin K Oral Anticoagulant Use and Cancer Incidence in Atrial Fibrillation Patients.

The association between the use of vitamin K antagonists (VKAs) and cancer risk reduction remains unclear. We aimed to assess the association between the use of VKAs or direct oral anticoagulants (DOACs) and the incidence of cancer in a large cohort of patients with atrial fibrillation (AF) by means of a population-based, propensity-weighted cohort study using population-wide databases including patients diagnosed with nonvalvular AF (NVAF) followed for up of 5 years (median 2.94 years). We created two cohorts based on the initiation therapy (VKA or DOAC). Initiation with VKA or DOAC was defined as filling a prescription with no previous exposure in the preceding 12 months. Cancer diagnoses of any type and for specific tumors (lung, colon, prostate, bladder, and breast). We included 39,989 patients, 31,200 (78.0%) in the VKA cohort. Incidence rate for any cancer was 12.45 per 1,000 person-year in the DOAC cohort vs. 14.55 in the VKA cohort (adjusted hazard ratio (HR): 1.16, 95% confidence interval (CI): 1.02-1.32). In secondary outcomes, no differences were found for specific types of cancer, such as lung (HR: 1.28, CI: 0.89-1.83), colon (HR: 0.84, CI: 0.62-1.13), prostate (HR: 1.40, CI: 0.94-2.10), bladder (HR: 1.07, CI: 0.76-1.52), and breast (HR: 1.05, CI: 0.66-1.69). Sensitivity analyses yielded similar results. Subgroup analyses also produced consistent findings, except for men, for whom VKA was associated with a lower risk of colon cancer (HR: 0.68, 95% CI: 0.48-0.96). Our results do not confirm a chemoprotective effect of VKA when compared with DOAC in a large, real-world cohort of patients with NVAF followed for up to 5 years.

Risk Assessment after ST-Segment Elevation Myocardial Infarction: Can Biomarkers Improve the Performance of Clinical Variables?

INTRODUCTION: Myocardial infarction with ST-segment elevation (STEMI) is the coronary artery disease associated with the highest risk of morbimortality; however, this risk is heterogeneous, usually being evaluated by clinical scores. Risk assessment is a key factor in personalized clinical management of patients with this disease. AIM: The aim of this study was to assess whether some new cardiac biomarkers considered alone, combined in a multibiomarker model or in association with clinical variables, improve the short- and long-term risk stratification of STEMI patients. MATERIALS AND METHODS: This was a retrospective observational study of 253 patients with STEMI. Blood samples were obtained before or during the angiography. The assessed biomarkers were C-terminal fragment of insulin-like growth factor binding protein-4 (CT-IGFBP4), high sensitive cardiac troponin T (hs-cTnT), N-terminal fragment of probrain natriuretic peptide (NT-proBNP), and growth differentiation factor 15 (GDF-15); they reflect different cardiovascular (CV) physiopathological pathways and underlying pathologies. We registered in-hospital and follow-up mortalities and their causes (cardiovascular and all-cause) and major adverse cardiac events (MACE) during a two year follow-up. Discrimination, survival analysis, model calibration, and reclassification of the biomarkers were comprehensively evaluated. RESULTS AND DISCUSSION: In total, 55 patients (21.7%) died, 33 in-hospital and 22 during the follow-up, most of them (69.1%) from CV causes; 37 MACE occurred during follow-up. Biomarkers showed good prognostic ability to predict mortality, alone and combined with the multibiomarker model. A predictive clinical model based on age, Killip-Kimball class, estimated glomerular filtration rate (eGFR), and heart rate was derived by multivariate analysis. GDF-15 and NT-proBNP significantly improved risk assessment of the clinical model, as shown by discrimination, calibration, and reclassification of all the end-points except for all-cause mortality. The combination of NT-proBNP and hs-cTnT improved CV mortality prediction. CONCLUSIONS: GDF-15 and NT-proBNP added value to the usual risk assessment of STEMI patients.

Differentiation of athlete's heart and hypertrophic cardiomyopathy by the fractal dimension of left ventricular trabeculae.

BACKGROUND: Differentiation between exercise induced adaptive myocardial hypertrophy (athlete's heart) and hypertrophic cardiomyopathy (HCM) is currently based on echocardiographic and cardiac magnetic resonance (CMR) criteria, but these may be insufficient in patients with subtle phenotype expression. This study aimed to assess whether left ventricular (LV) fractal pattern could permit to differentiate athlete's heart from HCM. METHODS: We recruited retrospectively 61 elite marathon runners, 67 patients with HCM, and 33 healthy subjects. A CMR study was performed in all subjects and the LV trabeculae fractal dimension (FD) was measured in end-diastolic frames of each short-axis cine sequence. For group comparison, the ratio of maximal myocardial wall thickness (mMWT)/indexed LV end-diastolic volume (LVED) was determined. RESULTS: As compared with athletes, patients with HCM had significantly (p < 0.001) greater FD in the LV basal (1.30 ± 0.07 vs. 1.23 ± 0.05) and apical (1.38 ± 0.06 vs. 1.30 ± 0.07) regions and in the whole heart (1.34 ± 0.05 vs. 1.27 ± 0.05). FD increased with age, left atrial area and indexed left ventricular mass (p < 0.05 for all) and correlated negatively with LV and RV end-diastolic volumes (p < 0.05 each). The addition of whole heart FD to the ratio of maximal myocardial wall thickness/indexed LVEDV lead to an improvement in the ability to discriminate HCM with a net reclassification index (NRI) of 71%. CONCLUSIONS: The FD regional distribution of the LV trabeculae differentiates patients with athlete's heart from patients with HCM. The addition of whole heart FD to the mMWT/indexed LVEDV ratio improves the predictive capacity of the model to differentiate both entities.

Phase angle by electrical bioimpedance is a predictive factor of hospitalisation, falls and mortality in patients with cirrhosis.

The phase angle is a versatile measurement to assess body composition, frailty and prognosis in patients with chronic diseases. In cirrhosis, patients often present alterations in body composition that are related to adverse outcomes. The phase angle could be useful to evaluate prognosis in these patients, but data are scarce. The aim was to analyse the prognostic value of the phase angle to predict clinically relevant events such as hospitalisation, falls, and mortality in patients with cirrhosis. Outpatients with cirrhosis were consecutively included and the phase angle was determined by electrical bioimpedance. Patients were prospectively followed to determine the incidence of hospitalisations, falls, and mortality. One hundred patients were included. Patients with phase angle ≤ 4.6° (n = 31) showed a higher probability of hospitalisation (35% vs 11%, p = 0.003), falls (41% vs 11%, p = 0.001) and mortality (26% vs 3%, p = 0.001) at 2-year follow-up than patients with PA > 4.6° (n = 69). In the multivariable analysis, the phase angle and MELD-Na were independent predictive factors of hospitalisation and mortality. Phase angle was the only predictive factor for falls. In conclusion, the phase angle showed to be a predictive marker for hospitalisation, falls, and mortality in outpatients with cirrhosis.

Modes of death in heart failure according to age, sex and left ventricular ejection fraction.

Modes of death in patients with heart failure (HF) have been well characterized in randomized studies, but data from real-life are scarce, especially in the elderly, women and in HF with mid-range or preserved left ventricular ejection fraction (LVEF). Our purpose was to examine modes of death in HF patients according to age, sex and LVEF. We analysed the mode of death of HF patients from two prospective multicentre contemporary Spanish registries conducted by cardiologists (REDINSCOR, n = 2150) and by internists (RICA, n = 1396). Mode of death was pre-specified. Out of 3546 patients, 485 (13.7%) died during the 9-month follow-up. Cardiovascular (CV) causes were the most frequent, regardless of the age, sex and LVEF. More than half of patients died due to worsening HF in both groups of patients, followed by other non-CV causes in those attended by internists, and sudden cardiac death in those cared by cardiologists. Stroke was more common among elderly patients, women and HF with preserved LVEF. Non-CV causes, particularly infectious diseases, accounted for a remarkable proportion of deaths, especially in the elderly and in HF patients with preserved LVEF. Functional class, age and anaemia had a strong influence on both CV and non-CV death. CV death due to refractory HF was the most prevalent among our population, irrespective of age, sex or LVEF. However, a significant proportion of HF patients died from non-CV causes, particularly elderly with mid-range and preserved LVEF. These patients could benefit significantly from a multidisciplinary follow-up.

A 3-Biomarker 2-Point-Based Risk Stratification Strategy in Acute Heart Failure.

Introduction and Objectives: Most multi-biomarker strategies in acute heart failure (HF) have only measured biomarkers in a single-point time. This study aimed to evaluate the prognostic yielding of NT-proBNP, hsTnT, Cys-C, hs-CRP, GDF15, and GAL-3 in HF patients both at admission and discharge. Methods: We included 830 patients enrolled consecutively in a prospective multicenter registry. Primary outcome was 12-month mortality. The gain in the C-index, calibration, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) was calculated after adding each individual biomarker value or their combination on top of the best clinical model developed in this study (C-index 0.752, 0.715-0.789) and also on top of 4 currently used scores (MAGGIC, GWTG-HF, Redin-SCORE, BCN-bioHF). Results: After 12-month, death occurred in 154 (18.5%) cases. On top of the best clinical model, the addition of NT-proBNP, hs-CRP, and GDF-15 above the respective cutoff point at admission and discharge and their delta during compensation improved the C-index to 0.782 (0.747-0.817), IDI by 5% (p < 0.001), and NRI by 57% (p < 0.001) for 12-month mortality. A 4-risk grading categories for 12-month mortality (11.7, 19.2, 26.7, and 39.4%, respectively; p < 0.001) were obtained using combination of these biomarkers. Conclusion: A model including NT-proBNP, hs-CRP, and GDF-15 measured at admission and discharge afforded a mortality risk prediction greater than our clinical model and also better than the most currently used scores. In addition, this 3-biomarker panel defined 4-risk categories for 12-month mortality.

A Mobile App (mHeart) to Detect Medication Nonadherence in the Heart Transplant Population: Validation Study.

BACKGROUND: Medication nonadherence in heart transplant recipients (HTxR) is related to graft loss and death. mHeart is a mobile app that uses electronic patient-reported outcome measures (ePROMs) to identify and manage medication nonadherence in the outpatient heart transplant (HTx) population. OBJECTIVE: The study primarily aimed to validate mHeart to measure medication nonadherence in early stage HTxR by assessing the psychometric properties of ePROMs. The secondary aims were to (1) measure patient satisfaction with the mHeart tool and its usability and (2) explore the impact of a theory-based treatment on medication nonadherence rates to determine its scalability to larger research. METHODS: A prospective study was conducted in the outpatient clinic of a tertiary hospital. All consecutive early stage HTxR (<1.5 years from HTx) were included. The ePROM psychometric properties assessed were validity, reliability, responsiveness, interpretability, and burden. ePROMs comprised the 4-item Morisky-Green-Levine questionnaire and an adapted version of the Haynes-Sackett questionnaire. The Simplified Medication Adherence Questionnaire (SMAQ) was also applied on-site. Three consecutive medication nonadherence assessments were performed by a transplant pharmacist. To improve medication nonadherence, theory-based interventions were delivered in a 1-month period. Patient satisfaction was assessed by a semiquantitative Web-based survey at the end of the study. RESULTS: We included 31 early stage HTxR (age: mean 54 years, SD 12 years), and 71% (22/31) of them were men. The HTxR were taking a mean 13 (SD 4; range 7-18) drugs per day. A total of 42% (13/31) of patients were unaware of the consequences of medication nonadherence, and 39% (12/31) of patients were nonadherent to immunosuppressive treatment. The content validity measure showed excellent levels of expert panel agreement for the Haynes-Sacket (14/14, 100%) and Morisky-Green-Levine (13/14, 93%) questionnaires. SMAQ and Morisky-Green-Levine ePROMs showed similar measurement domains (convergent validity, phi=0.6, P<.001), which, as expected, differed from Haynes-Sackett ePROMs (divergent validity, phi=0.3, P=.12). Reliability assessment revealed a very strong association between ePROM and on-site PROMs (phi>0.7, P<.001). Reproducibility was moderate (Haynes-Sackett κ=0.6, P<.002) or poor (Morisky-Green-Levine κ=0.3, P=.11) because of unexpected improved medication adherence rates during the test-retest period. According to responsiveness, the theory-based multifaceted intervention program improved medication nonadherence by 16% to 26% (P<.05). A burden analysis showed that ePROMs could potentially overcome traditional on-site limitations (eg, automatic recording of ePROM responses in the hospital information system). The mean score for overall patient satisfaction with the mHeart approach was 9 (SD 2; score range: 0-10). All 100% (29/29) of patients surveyed reported that they would recommend the mHeart platform to other HTxR. CONCLUSIONS: ePROMs adhered to the quality standards and successfully identified medication nonadherence in the HTx population, supporting their widespread use. The theory-based intervention program showed a promising improvement in medication adherence rates and produced excellent patient satisfaction and usability scores in HTxR.

Growth differentiation factor 15 as mortality predictor in heart failure patients with non-reduced ejection fraction.

AIMS: The prognostic value of biomarkers in patients with heart failure (HF) and mid-range (HFmrEF) or preserved ejection fraction (HFpEF) has not been widely addressed. The aim of this study was to assess whether the prognostic value of growth differentiation factor 15 (GDF-15) is superior to that of N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with HFmrEF or HFpEF. METHODS AND RESULTS: Heart failure patients with either HFpEF or HFmrEF were included in the study. During their first visit to the HF unit, serum samples were obtained and stored for later assessment of GDF-15 and NT-proBNP concentrations. Patients were followed up by the HF unit. The main endpoint was all-cause mortality. A total of 311 patients, 90 (29%) HFmrEF and 221 (71%) HFpEF, were included. Mean age was 72 ± 13 years, and 136 (44%) were women. No differences were found in GDF-15 or NT-proBNP concentrations between both HF groups. During a median follow-up of 15 months (Q1-Q3: 9-30 months), 98 patients (32%) died, most (71%) of cardiovascular causes. Patients who died had higher median concentrations of GDF-15 (4085 vs. 2270 ng/L, P < 0.0001) and NT-proBNP (1984 vs. 1095 ng/L, P < 0.0001). A Cox multivariable model identified New York Heart Association Functional Class III (P = 0.04), systolic blood pressure (P = 0.01), left atrial diameter (P = 0.03), age >65 years (P < 0.0001), and GDF-15 concentrations (P = 0.01) but not NT-proBNP as independent predictors of all-cause mortality. The area under the curve was 0.797 for the basic model including NT-proBNP, and the area under the curve comparing the overall model was 0.819, P = 0.016 (DeLong's test). Integrated discrimination improvement index after the inclusion of GDF-15 in the model with the mortality risk factors was 0.033; that is, the ability to predict death increased by 3.3% (P = 0.004). Net reclassification improvement was 0.548 (P < 0.001); that is, the capacity to improve the classification of the event (mortality) was 54.8%. GDF-15 concentrations were divided in tertiles (<1625, 1625-4330, and >4330 ng/L), and survival curves were evaluated using the Kaplan-Meier technique. Patients in the highest tertile had the poorest 5 year survival, at 16%, whereas the lowest tertile had the best survival, of 78% (P < 0.001). CONCLUSIONS: Growth differentiation factor 15 was superior to NT-proBNP for assessing prognosis in patients with HFpEF and HFmrEF. GDF-15 emerges as a strong, independent biomarker for identifying HFmrEF and HFpEF patients with worse prognosis.

Changes in causes of death and influence of therapeutic improvement over time in patients with heart failure and reduced ejection fraction.

INTRODUCTION AND OBJECTIVES: In patients with heart failure and reduced ejection fraction (HFrEF), several therapies have been proven to reduce mortality in clinical trials. However, there are few data on the effect of the use of evidence-based therapies on causes of death in clinical practice. METHODS: This study included 2351 outpatients with HFrEF (< 40%) from 2 multicenter prospective registries: MUSIC (n=641, period: 2003-2004) and REDINSCOR I (n=1710, period: 2007-2011). Variables were recorded at inclusion and all patients were followed-up for 4 years. Causes of death were validated by an independent committee. RESULTS: Patients in REDINSCOR I more frequently received beta-blockers (85% vs 71%; P <.001), mineralocorticoid antagonists (64% vs 44%; P <.001), implantable cardioverter-defibrillators (19% vs 2%; P <.001), and resynchronization therapy (7.2% vs 4.8%; P=.04). In these patients, sudden cardiac death was less frequent than in those in MUSIC (6.8% vs 11.4%; P <.001). After propensity score matching, we obtained 2 comparable populations differing only in treatments (575 vs 575 patients). In patients in REDINSCOR I, we found a lower risk of total mortality (HR, 0.70; 95%CI, 0.57-0.87; P=.001) and sudden cardiac death (sHR, 0.46; 95%CI, 0.30-0.70; P <.001), and a trend toward lower mortality due to end-stage HF (sHR, 0.73; 95%CI, 0.53-1.01; P=.059), without differences in other causes of death (sHR, 1.17; 95%CI, 0.78-1.75; P=.445), regardless of functional class. CONCLUSIONS: In ambulatory patients with HFrEF, implementation of evidence-based therapies was associated with a lower risk of death, mainly due to a significant reduction in sudden cardiac death.