Long-term, real world experience of ventricular tachycardia and granulomatous cardiomyopathy.

BACKGROUND: Granulomatous cardiomyopathy (GCM) is relatively uncommon in patients presenting with ventricular tachycardia (VT). Sarcoidosis and tuberculosis are the most common causes of GCM with VT. The aim of study was to evaluate their clinical characteristics and the long-term outcomes. METHODS: We retrospectively analyzed patients from March 2004 to January 2020, presenting with VT and subsequently diagnosed to have GCM. Patients were divided into three groups (sarcoid, tuberculosis and indeterminate) based on serologic tests, imaging and histopathology. The response to anti-arrhythmic and disease specific therapy on long-term follow-up were analyzed. RESULTS: There were 52 patients, comprising 27 males and 25 females, age 40 ± 10 years. The follow-up period was 5.9 ± 3.9 years. Sarcoidosis was diagnosed in 20 (38%); tuberculosis (TB) in 15(29%) and 17(33%) patients were indeterminate. Left ventricular ejection fraction (LVEF) of the entire cohort was 0.45 ± 0.14. Erythrocyte Sedimentation Rate(ESR) was found to be significantly higher in TB(43.6 ± 18.4) patients vs sarcoid(18.9 ± 6.7)p < 0.0001, but not the indeterminate group (36.2 ± 21.1), p = 0.3. Implantable Cardioverter Defibrillator (ICD) implantation was performed in 12/20(60%) patients in the sarcoid group, in 4/15(27%) patients in the TB group and in 10/17(59%) patients in the indeterminate group. At a mean follow-up of six years, VT recurrences were noted in 6, 2, and 7 patients in the sarcoid, TB and indeterminate groups respectively. CONCLUSION: Despite the advances in diagnostic modalities for tuberculosis and sarcoidosis, in real-world practice, almost one-third of the patients with VT and GCM have uncertain etiology. Long term outcomes of patients presenting with GCM and VT with mild left ventricle dysfunction treated appropriately seems favorable.

Association of obesity with heart failure outcomes in 11 Asian regions: A cohort study.

BACKGROUND: Asians are predisposed to a lean heart failure (HF) phenotype. Data on the 'obesity paradox', reported in Western populations, are scarce in Asia and have only utilised the traditional classification of body mass index (BMI). We aimed to investigate the association between obesity (defined by BMI and abdominal measures) and HF outcomes in Asia. METHODS AND FINDINGS: Utilising the Asian Sudden Cardiac Death in Heart Failure (ASIAN-HF) registry (11 Asian regions including Taiwan, Hong Kong, China, India, Malaysia, Thailand, Singapore, Indonesia, Philippines, Japan, and Korea; 46 centres with enrolment between 1 October 2012 and 6 October 2016), we prospectively examined 5,964 patients with symptomatic HF (mean age 61.3 ± 13.3 years, 26% women, mean BMI 25.3 ± 5.3 kg/m2, 16% with HF with preserved ejection fraction [HFpEF; ejection fraction ≥ 50%]), among whom 2,051 also had waist-to-height ratio (WHtR) measurements (mean age 60.8 ± 12.9 years, 24% women, mean BMI 25.0 ± 5.2 kg/m2, 7% HFpEF). Patients were categorised by BMI quartiles or WHtR quartiles or 4 combined groups of BMI (low, <24.5 kg/m2 [lean], or high, ≥24.5 kg/m2 [obese]) and WHtR (low, <0.55 [thin], or high, ≥0.55 [fat]). Cox proportional hazards models were used to examine a 1-year composite outcome (HF hospitalisation or mortality). Across BMI quartiles, higher BMI was associated with lower risk of the composite outcome (ptrend < 0.001). Contrastingly, higher WHtR was associated with higher risk of the composite outcome. Individuals in the lean-fat group, with low BMI and high WHtR (13.9%), were more likely to be women (35.4%) and to be from low-income countries (47.7%) (predominantly in South/Southeast Asia), and had higher prevalence of diabetes (46%), worse quality of life scores (63.3 ± 24.2), and a higher rate of the composite outcome (51/232; 22%), compared to the other groups (p < 0.05 for all). Following multivariable adjustment, the lean-fat group had higher adjusted risk of the composite outcome (hazard ratio 1.93, 95% CI 1.17-3.18, p = 0.01), compared to the obese-thin group, with high BMI and low WHtR. Results were consistent across both HF subtypes (HFpEF and HF with reduced ejection fraction [HFrEF]; pinteraction = 0.355). Selection bias and residual confounding are potential limitations of such multinational observational registries. CONCLUSIONS: In this cohort of Asian patients with HF, the 'obesity paradox' is observed only when defined using BMI, with WHtR showing the opposite association with the composite outcome. Lean-fat patients, with high WHtR and low BMI, have the worst outcomes. A direct correlation between high WHtR and the composite outcome is apparent in both HFpEF and HFrEF. TRIAL REGISTRATION: Asian Sudden Cardiac Death in HF (ASIAN-HF) Registry ClinicalTrials.gov Identifier: NCT01633398.

Effect of Ovarian Hormones and Mating Experience on the Preference of Female Mice to Investigate Male Urinary Pheromones.

In female mice, the expression of receptive lordosis behavior requires estradiol and progesterone actions in the nervous system; however, the contribution of these hormones to females' motivation to seek out male pheromones is less clear. In an initial experiment, sexually naïve ovary-intact female mice preferred to investigate (make nasal contact with) testes-intact male as opposed to estrous female urine, provided they were in vaginal estrus. In a second experiment, groups of sexually naïve and mating-experienced, ovariectomized females were tested for urinary pheromone preference first without and then with ovarian hormone replacement. Without hormone replacement, sexually naïve ovariectomized females showed no preference for male over female urinary pheromones whereas mating-experienced females preferred to investigate male pheromones. Ovariectomized females in both groups preferred male over female urine after sequential s.c. injections with estradiol benzoate followed 2 days later with progesterone and after prolonged (7 days) exposure to estradiol alone. Our results indicate that in sexually naïve female mice estradiol, perhaps aided by progesterone, is required to motivate a preference to seek out male pheromones whereas after mating experience females' preference to investigate male pheromones persists even in the absence of ovarian hormone action.

Real-world geographic variations in the use of cardiac implantable electronic devices-The PANORAMA 2 observational cohort study.

BACKGROUND: Currently, several geographies around the world remain underrepresented in medical device trials. The PANORAMA 2 study was designed to assess contemporary region-specific differences in clinical practice patterns of patients with cardiac implantable electronic devices (CIEDs). METHODS: In this prospective, multicenter, observational, multinational study, baseline and implant data of 4,706 patients receiving Medtronic CIEDs (Medtronic plc, Minneapolis, MN, USA; either de novo device implants, replacements, or upgrades) were analyzed, consisting of: 54% implantable pulse generators (IPGs), 20.3% implantable cardiac defibrillators (ICDs), 15% cardiac resynchronization therapy -defibrillators, and 5.1% cardiac resynchronization therapy -pacemakers, from 117 hospitals in 23 countries across four geographical regions between 2012 and 2016. RESULTS: For all device types, in all regions, there were fewer females than males enrolled, and women were less likely to have ischemic cardiomyopathy. Implant procedure duration differed significantly across the geographies for all device types. Subjects from emerging countries, women, and older patients were less likely to receive a magnetic resonance imaging-compatible device. Defibrillation testing differed significantly between the regions. European patients had the highest rates of atrial fibrillation (AF), and the lowest number of implanted single-chamber IPGs. Evaluation of stroke history suggested that the general embolic risk is more strongly associated with stroke than AF. CONCLUSIONS: We provide comprehensive descriptive data on patients receiving Medtronic CIEDs from several geographies, some of which are understudied in randomized controlled trials. We found significant variations in patient characteristics. Several medical decisions appear to be affected by socioeconomic factors. Long-term follow-up data will help evaluate if these variations require adjustments to outcome expectations.

Consensus statement for implantation and follow-up of cardiac implantable electronic devices in India.

Cardiac implantable electronic device (CIED) procedures are being done by many operators/centers and it is projected that this therapy will remarkably increase in India in the coming years. This document by IHRS, aims at guiding the Indian medical community in the appropriate use and method of implantation with emphasis on implanter training and center preparedness to deliver a safe and effective therapy to patients with cardiac rhythm disorders and heart failure.

A comparison of the effects of male pheromone priming and optogenetic inhibition of accessory olfactory bulb forebrain inputs on the sexual behavior of estrous female mice.

Previous research has shown that repeated testing with a stimulus male is required for ovariectomized, hormone-primed female mice to become sexually receptive (show maximal lordosis quotients; LQs) and that drug-induced, epigenetic enhancement of estradiol receptor function accelerated the improvement in LQs otherwise shown by estrous females with repeated testing. We asked whether pre-exposure to male pheromones ('pheromone priming') would also accelerate the improvement in LQs with repeated tests and whether optogenetic inhibition of accessory olfactory bulb (AOB) projection neurons could inhibit lordosis in sexually experienced estrous female mice. In Experiment 1, repeated priming with soiled male bedding failed to accelerate the progressive improvement in LQs shown by estrous female mice across 5 tests, although the duration of each lordosis response and females' investigation of male body parts during the first test was augmented by such priming. In Experiment 2, acute optogenetic inhibition of AOB inputs to the forebrain during freely moving behavioral tests significantly reduced LQs, suggesting that continued AOB signaling to the forebrain during mating is required for maximal lordotic responsiveness even in sexually experienced females. Our results also suggest that pheromonal stimulation, by itself, cannot substitute for the full complement of sensory stimulation received by estrous females from mounting males that normally leads to the progressive improvement in their LQs with repeated testing.

Quality-of-life outcomes with coronary artery bypass graft surgery in ischemic left ventricular dysfunction: a randomized trial.

BACKGROUND: The STICH (Surgical Treatment for Ischemic Heart Failure) trial compared a strategy of routine coronary artery bypass grafting (CABG) with guideline-based medical therapy for patients with ischemic left ventricular dysfunction. OBJECTIVE: To describe treatment-related quality-of-life (QOL) outcomes, a major prespecified secondary end point in the STICH trial. DESIGN: Randomized trial. (ClinicalTrials.gov: NCT00023595). SETTING: 99 clinical sites in 22 countries. PATIENTS: 1212 patients with a left ventricular ejection fraction of 0.35 or less and coronary artery disease. INTERVENTION: Random assignment to medical therapy alone (602 patients) or medical therapy plus CABG (610 patients). MEASUREMENTS: A battery of QOL instruments at baseline (98.9% complete) and 4, 12, 24, and 36 months after randomization (collection rates were 80% to 89% of those eligible). The principal prespecified QOL measure was the Kansas City Cardiomyopathy Questionnaire, which assesses the effect of heart failure on patients' symptoms, physical function, social limitations, and QOL. RESULTS: The Kansas City Cardiomyopathy Questionnaire overall summary score was consistently higher (more favorable) in the CABG group than in the medical therapy group by 4.4 points (95% CI, 1.8 to 7.0 points) at 4 months, 5.8 points (CI, 3.1 to 8.6 points) at 12 months, 4.1 points (CI, 1.2 to 7.1 points) at 24 months, and 3.2 points (CI, 0.2 to 6.3 points) at 36 months. Sensitivity analyses to account for the effect of mortality on follow-up QOL measurement were consistent with the primary findings. LIMITATION: Therapy was not masked. CONCLUSION: In this cohort of symptomatic high-risk patients with ischemic left ventricular dysfunction and multivessel coronary artery disease, CABG plus medical therapy produced clinically important improvements in quality of life compared with medical therapy alone over 36 months. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute.

Preparation of nanolignin rich fraction from bamboo stem via green technology: assessment of its antioxidant, antibacterial and UV blocking properties.

This work reports the preparation of nano lignin-rich fraction material via green technology from the holistic use of lignocellulosic biomass bamboo. The bamboo is first chemically treated, followed by acid precipitation to extract bamboo-derived macro lignin-rich fraction material. The nano lignin-rich fraction material was then prepared via ultrasonication technique from the extracted bamboo-derived macro lignin-rich fraction material. The confirmation of the distinct lignin functional groups in the extracted lignin-rich fractions has been done by FTIR. Surface morphology by FESEM and TEM revealed spherical nano-lignin-rich fraction materials from extracted bamboo-derived macro lignin-rich fraction materials. DPPH assays indicated that both the obtained fractions depict beneficial antioxidant characteristics. They were found to be effective in terms of their antibacterial activity against both gram-positive bacteria Staphylococcus aureus (S.aureus) and gram-negative bacteria Escherichia coli (E.coli), using the disc diffusion method. These fractions have UV blocking property, and nano-lignin-rich fraction material acts as a more potential UV blocking agent than others. Thus, the nano-lignin-rich fraction material has great potential as a high antioxidant, antibacterial, and UV blocking agent useful in biomedical applications.Highlights Extraction of macro-lignin rich fraction material using chemical treatment of lignocellulosic biomass bamboo via refluxing followed by acid precipitation.Preparation of nano-lignin rich fraction material from extracted bamboo-derived macro-lignin rich fraction material via ultrasonication technique as a green technology.Structural and surface morphology of the extracted macro-lignin & nano lignin-rich fraction materials have been analyzed by XRD, FTIR, EDX, SEM and TEM.The macro lignin & nano lignin-rich fraction materials showed good antioxidant, antibacterial activity and UV-blocking properties, but the nano-lignin rich fraction material exhibited more efficient properties.

Bamboo for producing charcoal and biochar for versatile applications.

Bamboo, the fastest-growing plant, has several unique characteristics that make it appropriate for diverse applications. It is low-cost, high-tensile, lightweight, flexible, durable, and capable of proliferating even in ineffectual areas (e.g., incline). This review discusses the unique properties of bamboo for making charcoal and biochar for diverse applications. To produce bamboo charcoal and biochar, this study reports on the pyrolysis process for the thermal degradation of organic materials in an oxygen-depleted atmosphere under a specific temperature. This is an alternative method for turning waste biomass into products with additional value, such as biochar. Due to various advantages, bamboo charcoal is preferred over regular charcoal as it has four times the absorption rate and ten times more surface area reported. According to the reports, the charcoal yield ranges from 24.60 to 74.27%. Bamboo chopsticks were the most useful source for producing charcoal, with a high yield of 74.27% at 300 °C in nitrogen, but the thorny bamboo species have a tremendous amount of minimal charcoal, i.e., 24.60%. The reported biochar from bamboo yield ranges from 32 to 80%. The most extensive biochar production is produced by the bamboo D. giganteus, which yields 80% biochar at 300 °C. Dry bamboo stalks at 400 °C produced 32% biochar. One of the sections highlights biochar as a sustainable solution for plastic trash management produced during the COVID-19 pandemic. Another section is dedicated to the knowledge enhancement about the broad application spectrum of the charcoal and biochar. The last section highlights the conclusions, future perspectives, and recommendations on the charcoal and biochar derived from bamboo.

Patient-Reported Status and Heart Failure Outcomes in Asia by Sex, Ethnicity, and Socioeconomic Status.

Background: In heart failure (HF), symptoms and health-related quality of life (HRQoL) are known to vary among different HF subgroups, but evidence on the association between changing HRQoL and outcomes has not been evaluated. Objectives: The authors sought to investigate the relationship between changing symptoms, signs, and HRQoL and outcomes by sex, ethnicity, and socioeconomic status (SES). Methods: Using the ASIAN-HF (Asian Sudden Cardiac Death in Heart Failure) Registry, we investigated associations between the 6-month change in a "global" symptoms and signs score (GSSS), Kansas City Cardiomyopathy Questionnaire overall score (KCCQ-OS), and visual analogue scale (VAS) and 1-year mortality or HF hospitalization. Results: In 6,549 patients (mean age: 62 ± 13 years], 29% female, 27% HF with preserved ejection fraction), women and those in low SES groups had higher symptom burden but lower signs and similar KCCQ-OS to their respective counterparts. Malay patients had the highest GSSS (3.9) and lowest KCCQ-OS (58.5), and Thai/Filipino/others (2.6) and Chinese patients (2.7) had the lowest GSSS scores and the highest KCCQ-OS (73.1 and 74.6, respectively). Compared to no change, worsening of GSSS (>1-point increase), KCCQ-OS (≥10-point decrease) and VAS (>1-point decrease) were associated with higher risk of HF admission/death (adjusted HR: 2.95 [95% CI: 2.14-4.06], 1.93 [95% CI: 1.26-2.94], and 2.30 [95% CI: 1.51-3.52], respectively). Conversely, the same degrees of improvement in GSSS, KCCQ-OS, and VAS were associated with reduced rates (HR: 0.35 [95% CI: 0.25-0.49], 0.25 [95% CI: 0.16-0.40], and 0.64 [95% CI: 0.40-1.00], respectively). Results were consistent across all sex, ethnicity, and SES groups (interaction P > 0.05). Conclusions: Serial measures of patient-reported symptoms and HRQoL are significant and consistent predictors of outcomes among different groups with HF and provide the potential for a patient-centered and pragmatic approach to risk stratification.

Ventricular Tachycardia Storm in Cardiac Sarcoidosis: A 76-Day-ICU-Nightmare.

Ventricular Tachycardia (VT) is a life threatening complication in a patient with Cardiac Sarcoidosis. The management becomes extremely challenging when it is refractory to traditional anti-arrhythmic drugs. Herein, we describe a case where a 33-year-old patient with VT storm, with an implantable cardioverter defibrillator (ICD), was managed by medications, sedation, ventilator support and multiple Radio-Frequency (RF) ablation procedures over 76-days ICU stay period.

Identifying high risk patients post myocardial infarction with reduced left ventricular function using loop recorders INSPIRE-ELR clinical study.

AIMS: Sudden cardiac death (SCD) continues to be a devastating complication amongst survivors of myocardial infarction (MI). Mortality is high in the initial months after MI. The aims of the INSPIRE-ELR study were to assess the proportion of patients with significant arrhythmias early after MI and the association with mortality during 12 months of follow-up. METHODS: The study included 249 patients within 14 days after MI with left ventricular ejection fraction (LVEF) ≤35% at discharge in 11 hospitals in India. Patients received a wearable external loop recorder (ELR) 5 ± 3 days after MI to monitor arrhythmias for 7 days. RESULTS: Patients were predominantly male (86%) with a mean age of 56 ± 12 years. In 82%, reperfusion had been done and all received standard of care cardiovascular medications at discharge. LVEF was 32.2 ± 3.9%, measured 5.1 ± 3.0 days after MI. Of the 233 patients who completed monitoring (7.1 ± 1.5 days), 81 (35%) experienced significant arrhythmias, including Ventricular Tachycardia/Fibrillation (VT/VF): 10 (4.3%); frequent Premature Ventricular Contractions (PVCs): 65 (28%); Atrial Fibrillation (AF): 8 (3.4%); chronic atrial flutter: 4 (1.7%); 2nd or 3rd degree Atrioventricular (AV) block: 4 (1.7%); and symptomatic bradycardia: 8 (3.4%). In total, 26 patients died. Mortality was higher in patients with clinically significant arrhythmia (at 12 months: 23.6% vs 4.8% with 19 vs 7 deaths, hazard ratio (HR) = 5.5, 95% confidence interval (CI) 2.3 to 13.0, p < 0.0001). Excluding 7 deaths during ELR monitoring, HR = 4.5, p < 0.001. CONCLUSION: ELR applied in patients with acute MI and LV dysfunction at the time of discharge identifies patients with high mortality risk.

Interventions in the diagnosis and adoption of pacemaker therapy in sinus node dysfunction patients: Results from the IMPROVE Brady study.

AIMS: IMPROVE Brady assessed whether a process improvement intervention could increase adoption of guideline-based therapy in sinus node dysfunction (SND) patients. METHODS: /Results: IMPROVE Brady was a sequential, prospective, quality improvement initiative conducted in India and Bangladesh. Patients with symptomatic bradycardia were enrolled. In Phase I, physicians assessed and treated patients per standard care. Phase II began after implementing educational materials for physicians and patients. Primary objectives were to evaluate the impact of the intervention on SND diagnosis and pacemaker (PPM) implant. SF-12 quality of life (QoL) and Zarit burden surveys were collected pre- and post-PPM implant. A total of 978 patients were enrolled (57.7 ± 14.8 years, 75% male), 508 in Phase I and 470 in Phase II. The diagnosis of SND and implantation of PPM increased significantly from Phase I to Phase II (72% vs. 87%, P < 0.001 and 17% vs. 32%, P < 0.001, respectively). Pacemaker implantation was not feasible in 41% of patients due to insurance/cost barriers which was unaltered by the intervention. Both patient QoL and caregiver burden improved at 6-months post-PPM implant (P < 0.001). CONCLUSIONS: A process improvement initiative conducted at centers across India and Bangladesh significantly increased the diagnosis of SND and subsequent treatment with PPM therapy despite the socio-economic constraints.

2021 Asia Pacific Heart Rhythm Society (APHRS) practice guidance on atrial fibrillation screening.

In this paper, the Asia Pacific Heart Rhythm Society (APHRS) sought to provide practice guidance on AF screening based on recent evidence, with specific considerations relevant to the Asia-Pacific region. A key recommendation is opportunistic screening for people aged ≥65 years (all countries), with systematic screening to be considered for people aged ≥75 years or who have additional risk factors (all countries).

Congenital cystic adenomatoid malformation in an adolescent: an unusual presentation with pleural effusion and pneumatocele.

Congenital cystic adenomatoid malformation (CCAM) encompasses a continuum of hamartomatous cystic lung lesions characterised by the presence of abnormal bronchiolar structures of varying sizes or distribution. The CCAM is a disorder of infancy with majority of the cases being diagnosed within the first two years of life. We describe CCAM in a 13-year-old girl complaining of recurrent lower respiratory tract infections since infancy who presented with post-infectious pneumatocele with loculated pleural effusion, and suspected abscess formation and had undergone resection.

Beta blockers in arrhythmias: when and where to use?

Beta blockers are often the first line of medications used in treatment of arrhythmias. Their role has been established in treatment of Supraventricular tachycardia (SVT) and Ventricular tachyarrhythmias (VT). Beta Blockers are also used as prophylactic medications in SVT, VT and Sudden Cardiac Arrest survivors. They are important components of treatment in the management of VT storms, Atrial Fibrillation, arrhythmias during pregnancy, arrhythmias associated with congenital heart disease, Long QT syndrome, arrhythmias in cardiomyopathies and post-cardiac surgery arrhythmias.The choice of drug, dose and route of administration depends on the type of arrhythmia and clinical presentation and demographics of the patient.

Regional Variation of Mortality in Heart Failure With Reduced and Preserved Ejection Fraction Across Asia: Outcomes in the ASIAN-HF Registry.

Background Data comparing outcomes in heart failure (HF) across Asia are limited. We examined regional variation in mortality among patients with HF enrolled in the ASIAN-HF (Asian Sudden Cardiac Death in Heart Failure) registry with separate analyses for those with reduced ejection fraction (EF; <40%) versus preserved EF (≥50%). Methods and Results The ASIAN-HF registry is a prospective longitudinal study. Participants with symptomatic HF were recruited from 46 secondary care centers in 3 Asian regions: South Asia (India), Southeast Asia (Thailand, Malaysia, Philippines, Indonesia, Singapore), and Northeast Asia (South Korea, Japan, Taiwan, Hong Kong, China). Overall, 6480 patients aged >18 years with symptomatic HF were recruited (mean age: 61.6±13.3 years; 27% women; 81% with HF and reduced rEF). The primary outcome was 1-year all-cause mortality. Striking regional variations in baseline characteristics and outcomes were observed. Regardless of HF type, Southeast Asians had the highest burden of comorbidities, particularly diabetes mellitus and chronic kidney disease, despite being younger than Northeast Asian participants. One-year, crude, all-cause mortality for the whole population was 9.6%, higher in patients with HF and reduced EF (10.6%) than in those with HF and preserved EF (5.4%). One-year, all-cause mortality was significantly higher in Southeast Asian patients (13.0%), compared with South Asian (7.5%) and Northeast Asian patients (7.4%; P<0.001). Well-known predictors of death accounted for only 44.2% of the variation in risk of mortality. Conclusions This first multinational prospective study shows that the outcomes in Asian patients with both HF and reduced or preserved EF are poor overall and worst in Southeast Asian patients. Region-specific risk factors and gaps in guideline-directed therapy should be addressed to potentially improve outcomes. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01633398.

Effects of combined renin-angiotensin-aldosterone system inhibitor and beta-blocker treatment on outcomes in heart failure with reduced ejection fraction: insights from BIOSTAT-CHF and ASIAN-HF registries.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) and ß-blockers are guideline-recommended first-line therapies in heart failure (HF) with reduced ejection fraction (HFrEF). Previous studies showed that individual drug classes were under-dosed in many parts of Europe and Asia. In this study, we investigated the association of combined up-titration of ACEi/ARBs and ß-blockers with all-cause mortality and its combination with hospitalization for HF. METHODS AND RESULTS: A total of 6787 HFrEF patients (mean age 62.6 ± 13.2 years, 77.7% men, mean left ventricular ejection fraction 27.7 ± 7.2%) were enrolled in the prospective multinational European (BIOSTAT-CHF; n = 2100) and Asian (ASIAN-HF; n = 4687) studies. Outcomes were analysed according to achieved percentage of guideline-recommended target doses (GRTD) of combination ACEi/ARB and ß-blocker therapy, adjusted for indication bias. Only 14% (n = 981) patients achieved ≥50% GRTD for both ACEi/ARB and ß-blocker. The best outcomes were observed in patients who achieved 100% GRTD of both ACEi/ARB and ß-blocker [hazard ratio (HR) 0.32, 95% confidence interval (CI) 0.26-0.39 vs. none]. Lower dose of combined therapy was associated with better outcomes than 100% GRTD of either monotherapy. Up-titrating ß-blockers was associated with a consistent and greater reduction in hazards of all-cause mortality (HR for 100% GRTD: 0.40, 95% CI 0.25-0.63) than corresponding ACEi/ARB up-titration (HR 0.75, 95% CI 0.53-1.07). CONCLUSION: This study shows that best outcomes were observed in patients attaining GRTD for both ACEi/ARB and ß-blockers, unfortunately this was rarely achieved. Achieving >50% GRTD of both drug classes was associated with better outcome than target dose of monotherapy. Up-titrating ß-blockers to target dose was associated with greater mortality reduction than up-titrating ACEi/ARB.