In vitro evidence against productive SARS-CoV-2 infection of human testicular cells: Bystander effects of infection mediate testicular injury.

The hallmark of severe COVID-19 involves systemic cytokine storm and multi-organ injury including testicular inflammation, reduced testosterone, and germ cell depletion. The ACE2 receptor is also expressed in the resident testicular cells, however, SARS-CoV-2 infection and mechanisms of testicular injury are not fully understood. The testicular injury could be initiated by direct virus infection or exposure to systemic inflammatory mediators or viral antigens. We characterized SARS-CoV-2 infection in different human testicular 2D and 3D culture systems including primary Sertoli cells, Leydig cells, mixed seminiferous tubule cells (STC), and 3D human testicular organoids (HTO). Data shows that SARS-CoV-2 does not productively infect any testicular cell type. However, exposure of STC and HTO to inflammatory supernatant from infected airway epithelial cells and COVID-19 plasma decreased cell viability and resulted in the death of undifferentiated spermatogonia. Further, exposure to only SARS-CoV-2 Envelope protein caused inflammatory response and cytopathic effects dependent on TLR2, while Spike 1 or Nucleocapsid proteins did not. A similar trend was observed in the K18-hACE2 transgenic mice which demonstrated a disrupted tissue architecture with no evidence of virus replication in the testis that correlated with peak lung inflammation. Virus antigens including Spike 1 and Envelope proteins were also detected in the serum during the acute stage of the disease. Collectively, these data strongly suggest that testicular injury associated with SARS-CoV-2 infection is likely an indirect effect of exposure to systemic inflammation and/or SARS-CoV-2 antigens. Data also provide novel insights into the mechanism of testicular injury and could explain the clinical manifestation of testicular symptoms associated with severe COVID-19.

Understanding repeat hospitalizations in intermediate-to-high risk aortic stenosis patients following transcatheter aortic valve replacement.

OBJECTIVES: We describe the causes, timing and predictors of readmissions and analyze its impact on clinical outcomes in intermediate-to-high-risk patients with severe symptomatic aortic stenosis (AS) who underwent transcatheter aortic valve replacement (TAVR). BACKGROUND: Intermediate-high risk TAVR patients with severe AS have an increased risk for hospital readmissions due to the high burden of comorbidities. METHODS: Patients who underwent TAVR from 2012 to 2018 at a single tertiary cardiac center were included and followed for 1 year. Readmissions were categorized as noncardiovascular (non-CV) and CV. RESULTS: A total of 611 patients (410 with no readmissions, 201 with ≥1 readmissions) were included. There was a total of 317 readmissions (mean: 1.58 ± 1.09 per readmitted patient) with 65 patients having ≥2 readmissions. 64.0% were non-CV and 36.0% were CV. The top three CV causes were pacemaker/implantable cardioverter-defibrillator placement, bleeding, and stroke. About 23% occurred at 1 m, the majority were CV; 45% occurred between 7 and 12 m, the majority were non-CV. Those with ≥1 readmissions had a higher burden of comorbidities including peripheral arterial disease, diabetes, immunosuppression, prior percutaneous coronary interventions, and dialysis. Readmissions were associated with higher 1-year mortality (adjusted hazard ratio: 2.53, 95% confidence interval: 1.40-4.59; p = 0.002). High-risk patients had higher non-CV readmissions (0.37 ± 0.79 vs. 0.25 ± 0.62; p = 0.044) compared to intermediate-risk patients but similar CV readmissions (p = 0.645). CONCLUSIONS: Understanding readmissions post-TAVR will promote the early identification of at-risk groups and the implementation of preventative measures to improve outcomes and reduce the burden and costs of readmissions.

High-Resolution Digital Phenotypes From Consumer Wearables and Their Applications in Machine Learning of Cardiometabolic Risk Markers: Cohort Study.

BACKGROUND: Consumer-grade wearable devices enable detailed recordings of heart rate and step counts in free-living conditions. Recent studies have shown that summary statistics from these wearable recordings have potential uses for longitudinal monitoring of health and disease states. However, the relationship between higher resolution physiological dynamics from wearables and known markers of health and disease remains largely uncharacterized. OBJECTIVE: We aimed to derive high-resolution digital phenotypes from observational wearable recordings and to examine their associations with modifiable and inherent markers of cardiometabolic disease risk. METHODS: We introduced a principled framework to extract interpretable high-resolution phenotypes from wearable data recorded in free-living conditions. The proposed framework standardizes the handling of data irregularities; encodes contextual information regarding the underlying physiological state at any given time; and generates a set of 66 minimally redundant features across active, sedentary, and sleep states. We applied our approach to a multimodal data set, from the SingHEART study (NCT02791152), which comprises heart rate and step count time series from wearables, clinical screening profiles, and whole genome sequences from 692 healthy volunteers. We used machine learning to model nonlinear relationships between the high-resolution phenotypes on the one hand and clinical or genomic risk markers for blood pressure, lipid, weight and sugar abnormalities on the other. For each risk type, we performed model comparisons based on Brier scores to assess the predictive value of high-resolution features over and beyond typical baselines. We also qualitatively characterized the wearable phenotypes for participants who had actualized clinical events. RESULTS: We found that the high-resolution features have higher predictive value than typical baselines for clinical markers of cardiometabolic disease risk: the best models based on high-resolution features had 17.9% and 7.36% improvement in Brier score over baselines based on age and gender and resting heart rate, respectively (P<.001 in each case). Furthermore, heart rate dynamics from different activity states contain distinct information (maximum absolute correlation coefficient of 0.15). Heart rate dynamics in sedentary states are most predictive of lipid abnormalities and obesity, whereas patterns in active states are most predictive of blood pressure abnormalities (P<.001). Moreover, in comparison with standard measures, higher resolution patterns in wearable heart rate recordings are better able to represent subtle physiological dynamics related to genomic risk for cardiometabolic disease (improvement of 11.9%-22.0% in Brier scores; P<.001). Finally, illustrative case studies reveal connections between these high-resolution phenotypes and actualized clinical events, even for borderline profiles lacking apparent cardiometabolic risk markers. CONCLUSIONS: High-resolution digital phenotypes recorded by consumer wearables in free-living states have the potential to enhance the prediction of cardiometabolic disease risk and could enable more proactive and personalized health management.

Atrial Fibrillation and the Prognostic Performance of Biomarkers in Heart Failure.

BACKGROUND: Consideration of circulating biomarkers for risk stratification in heart failure (HF) is recommended, but the influence of atrial fibrillation (AF) on prognostic performance of many markers is unclear. We investigated the influence of AF on the prognostic performance of circulating biomarkers in HF. METHODS: N-terminal pro-B-type natriuretic peptide (NT-proBNP), mid-regional-pro-atrial natriuretic peptide, C-type natriuretic peptide (CNP), NT-proCNP, high-sensitivity troponin-T, high-sensitivity troponin-I, mid-regional-propeptide adrenomedullin, co-peptin, growth differentiation factor-15, soluble Suppressor of Tumorigenicitiy (sST2), galectin-3, and procalcitonin plasma concentrations were measured in a prospective, multicenter study of adults with HF. AF was defined as a previous history of AF, and/or presence of AF/flutter on baseline 12-lead electrocardiogram. The primary outcome was the composite of HF-hospitalization or all-cause mortality at 2 years. RESULTS: Among 1099 patients (age 62 ± 12years, 28% female), 261(24%) patients had AF. Above-median concentrations of all biomarkers were independently associated with increased risk of the primary outcome. Significant interactions with AF were detected for galectin-3 and sST2. In considering NT-proBNP for additive risk stratification, sST2 (adjusted hazard ratio [AHR]1.85, 95%confidence interval [C.I.] 1.17-2.91) and galectin-3 (AHR1.85, 95%C.I. 1.09-2.45) were independently associated with increased primary outcome only in the presence of AF. The prognostic performance of sST2 was also stronger in AF for all-cause mortality (AF: AHR2.82, 95%C.I. 1.26-6.21; non-AF: AHR1.78, 95% C.I. 1.14-2.76 without AF), while galectin-3 predicted HF-hospitalization only in AF (AHR1.64, 95%C.I. 1.03-2.62). CONCLUSIONS: AF modified the prognostic utility of selected guideline-endorsed HF-biomarkers. Application of markers for prognostic purposes in HF requires consideration of the presence or absence of AF. CLINICAL TRIAL REGISTRATION: ACTRN12610000374066.

Predicting Coronary Artery Disease in Primary Care: Development and Validation of a Diagnostic Risk Score for Major Ethnic Groups in Southeast Asia.

BACKGROUND: Coronary artery disease (CAD) risk prediction tools are useful decision supports. Their clinical impact has not been evaluated amongst Asians in primary care. OBJECTIVE: We aimed to develop and validate a diagnostic prediction model for CAD in Southeast Asians by comparing it against three existing tools. DESIGN: We prospectively recruited patients presenting to primary care for chest pain between July 2013 and December 2016. CAD was diagnosed at tertiary institution and adjudicated. A logistic regression model was built, with validation by resampling. We validated the Duke Clinical Score (DCS), CAD Consortium Score (CCS), and Marburg Heart Score (MHS). MAIN MEASURES: Discrimination and calibration quantify model performance, while net reclassification improvement and net benefit provide clinical insights. KEY RESULTS: CAD prevalence was 9.5% (158 of 1658 patients). Our model included age, gender, type 2 diabetes mellitus, hypertension, smoking, chest pain type, neck radiation, Q waves, and ST-T changes. The C-statistic was 0.808 (95% CI 0.776-0.840) and 0.815 (95% CI 0.782-0.847), for model without and with ECG respectively. C-statistics for DCS, CCS-basic, CCS-clinical, and MHS were 0.795 (95% CI 0.759-0.831), 0.756 (95% CI 0.717-0.794), 0.787 (95% CI 0.752-0.823), and 0.661 (95% CI 0.621-0.701). Our model (with ECG) correctly reclassified 100% of patients when compared with DCS and CCS-clinical respectively. At 5% threshold probability, the net benefit for our model (with ECG) was 0.063. The net benefit for DCS, CCS-basic, and CCS-clinical was 0.056, 0.060, and 0.065. CONCLUSIONS: PRECISE (Predictive Risk scorE for CAD In Southeast Asians with chEst pain) performs well and demonstrates utility as a clinical decision support for diagnosing CAD among Southeast Asians.

Adjunctive use of fluoroscopy during MitraClip implantation reduces procedural complexity: The parallax technique.

BACKGROUND: During MitraClip implantation sub-valvular correction of trajectory and/or alignment may increase adverse clip or leaflet events. With systematic adjunctive use of fluoroscopy ("Parallax technique"), we aimed to assess parameters that minimize the need for corrective measures and help increase procedural efficiency. METHODS: We retrospectively analyzed 30 patients without (Fl-) and 39 patients utilizing adjunctive fluoroscopy (Fl+) during MitraClip implantation. After establishing trajectory and supra-valvular alignment, the Parallax technique was utilized. Trajectory and alignment are maintained during advancement. RESULTS: All patients had 3 or 4+ MR. There were no differences in baseline demographics. The average number of clips (Fl- vs Fl+) was 1.72 ± 0.8 vs 1.59 ± 0.5, p = .57. For the first clip, the need for sub-valvular alignment (80% vs. 36%, p = .0001), eversion with retraction back to left atrium (23% vs. 10%, p = .001) and the number of grasps (2.3 ± 1.2 vs 1.4 ± 0.9) was reduced. The time from transseptal puncture to first clip deployment (71 ± 21 vs 44 ± 16 min, p = .01) was reduced. Procedural success was achieved in all but one patient in the Fl- group (p = ns). There were no differences noted for in-hospital or 30-day outcomes. CONCLUSIONS: Systematic use of a simple and easy to implement "Parallax technique" was associated with reduced need for sub-valvular manipulation and was associated with improved procedural times. Further larger scale studies are needed to assess the applicability of the technique.

Beyond fitness tracking: The use of consumer-grade wearable data from normal volunteers in cardiovascular and lipidomics research.

The use of consumer-grade wearables for purposes beyond fitness tracking has not been comprehensively explored. We generated and analyzed multidimensional data from 233 normal volunteers, integrating wearable data, lifestyle questionnaires, cardiac imaging, sphingolipid profiling, and multiple clinical-grade cardiovascular and metabolic disease markers. We show that subjects can be stratified into distinct clusters based on daily activity patterns and that these clusters are marked by distinct demographic and behavioral patterns. While resting heart rates (RHRs) performed better than step counts in being associated with cardiovascular and metabolic disease markers, step counts identified relationships between physical activity and cardiac remodeling, suggesting that wearable data may play a role in reducing overdiagnosis of cardiac hypertrophy or dilatation in active individuals. Wearable-derived activity levels can be used to identify known and novel activity-modulated sphingolipids that are in turn associated with insulin sensitivity. Our findings demonstrate the potential for wearables in biomedical research and personalized health.

Assessing the Impact of Transcatheter Aortic Valve Implantation on Cardiac Catheterisation: A Multicentric Study.

BACKGROUND: The success rate of coronary angiography (CA) after transcatheter aortic valve implantation (TAVI) is variable. Our aim was to investigate CA difficulty, outcomes, and predictors of difficult CA after TAVI. METHOD: This was an international multicentric retrospective cohort study that included patients with TAVI and subsequent CA between January 2010 and December 2019. Difficulty with CA was graded as 1 (normal), 2 (partial engagement, complete vessel opacification), 3 (partial engagement, incomplete vessel opacification), and 4 (unsuccessful angiography). Patients were grouped as (a) "easy" (grade 1 for left and right) or (b) "difficult" (grade >1 for either). We compared baseline characteristics and outcomes, and performed multivariate logistic regression for predictors of difficult CA. RESULTS: Of 96 patients included (mean age 77.4±8.7 years, 48 [50%] male), 88 (92%) had successful CA. Right CA was successful in 80 (83%) patients and left CA in 91 (95%) (p<0.0001). The "difficult" group (n=41 [43%]) had higher Society of Thoracic Surgery (STS) scores (7.6±4.9 vs 5.4±4.0; p=0.022), smaller annulus perimeters (72.4±5.4 mm vs 76.2±9.4 mm; p=0.049), greater use of self-expanding valves (83% vs 18%; p<0.0001), increased valve size (26.8±2.1 mm vs 25.6±3.0 mm; p=0.032), and increased oversizing for area (44.3%±17.4% vs 23.6%±22.0%; p=0.0002) and perimeter (17.5%±8.2% vs 7.1%±10.8%; p<0.0001). There was no difference in outcomes except for increased major bleeding (7.3% vs 0.0%; p=0.042). The strongest predictor for "difficult" CA was self-expanding valves when compared to balloon-expandable valves (adjusted odds ratio [aOR], 15.23; 95% confidence interval [CI], 2.27-102.40). Society of Thoracic Surgery score was borderline predictive (aOR, 1.26; 95% CI, 1.04-1.52). CONCLUSIONS: Our results show that after TAVI, CA success rate is high, right CA is more difficult than left, self-expanding valves predispose to difficult CA, and STS score weakly predicts difficult CA. This study is hypothesis-generating and more research is required to confirm these findings.

Transjugular mitral valve repair with the MitraClip: A step-by-step guide.

The MitraClip procedure is carried out almost exclusively via the transfemoral approach. However, in some patients transfemoral delivery of MitraClip is not technically feasible (e.g., occluded inferior vena cava or tortuous/obstructive iliofemoral venous anatomy). The technical considerations and challenges of the MitraClip procedure are amplified when an alternate route is considered. We describe a successful case of MitraClip performed via the right internal jugular (IJ) approach in a patient with a flail A3 scallop and previous mitral valve repair. We reviewed prior cases in the literature and discuss step-by-step the pertinent clinical and technical considerations for performing this procedure via the transjugular route. In summary, the right IJ access site provides a reasonable alternative to perform the MitraClip procedure in cases where femoral access is contraindicated or prohibitive. A thorough understanding of the technical considerations is crucial in improving procedural success rates.

Transseptal access for left heart structural interventions in the setting of prior atrial septal defect closure.

A transseptal puncture is critical for "left-sided" structural heart interventions. Procedures such as transcatheter edge-to-edge repair (MitraClip) and left atrial appendage (LAA) closure (Watchman) require precise puncture of the interatrial septum (IAS), and the presence of a prior atrial septal defect (ASD) closure device poses a challenge. We aim to present a successfully completed case of MitraClip and Watchman in the presence of ASD closure device in two different patients. A review of the literature will be reported, and pertinent clinical and technical considerations will be discussed in depth to achieve procedural success. In summary, transseptal puncture for left heart structural interventions is feasible in the presence of a prior ASD/patent foramen ovale closure device. A detailed understanding of the anatomical considerations as well as the use of multimodality imaging to evaluate the IAS will aid in improving procedural success rates.

A randomized controlled trial on the effectiveness of a portable patient education video prior to coronary angiography and angioplasty.

INTRODUCTION: Time limitations in busy clinical settings may impede adequate explanation of coronary angiography/angioplasty. We aim to evaluate the effectiveness of a portable patient education video in improving knowledge and allaying patient's anxiety. METHODS: Consecutive patients undergoing coronary angiography/angioplasty were prospectively recruited over 1 year from a tertiary cardiac institution. A 3-min animated patient education video on the procedure was developed to be shown on a tablet. Patients were randomized 3:1 into an intervention group (video plus routine care) versus a control group (routine care). Before the procedure, a self-administered questionnaire was conducted in both groups. The questionnaire was repeated post-video in the intervention group. RESULTS: A total of 332 patients (252 intervention groups, 80 controls) were recruited. At baseline, the intervention group had lower knowledge scores (p = .022) and similar anxiety scores (p = .323) compared with the control group. After the video, the intervention group had significantly higher knowledge scores (p ≤ .001) and lower anxiety scores (p ≤ .001). Within the intervention group, there was a significant increase in knowledge scores (p ≤ .001) and reduction in anxiety scores (p ≤ .001) before versus after watching the video. In the subset of patients who had previously undergone a similar procedure (n = 131), there was also significant improvement in knowledge scores and reduction in anxiety scores (p < .001). The video is accessible at https://youtu.be/R8AdaIbNq7Y. CONCLUSION: The video improved knowledge and reduced anxiety in patients undergoing coronary angiography and angioplasty. This is a useful adjunct to incorporate into existing workflows to improve patient care.

E/e' in relation to outcomes in ST-elevation myocardial infarction.

BACKGROUND: Myocardial infarction (MI) is a high-risk condition especially when filling pressure is raised, and earlier reports have suggested that E/e' is associated with poor outcome. However, whether E/e' predicts risk better than LVEF, which is the current standard of practice, is not known. We investigated this question in the largest and most rigorous study of MI patients so far. METHODS AND RESULTS: We studied 660 patients with ST-elevation MI (STEMI) treated with primary percutaneous coronary intervention and related E/e' to short-term mortality (in-hospital death), as well as long-term events at 2 years comprising (a) a composite of MI, stroke, heart failure, and death, and (b) death alone. Short-term models were adjusted for age, sex, and LVEF. Long-term models were adjusted for age, sex, diabetes, revascularization procedure, history of MI, hypertension, renal function, drugs on discharge, and LVEF. Elevated E/e'> 15 indicated higher risk of short-term events (n = 19:7.0% (95% confidence interval 3.4-10.8%) vs. 1.0% (0.3 - 2.3%); adjusted odds ratio 3.7 (1.3-10.5)). While elevated E/e' was also associated with long-term outcomes (n = 103 composite events: 15.9% (11.9% - 21.4%) vs 6.8% (5.2% - 8.7%), P < .001; n = 38 death events: 6.0% (3.9% - 9.5%) vs 2.0% (1.3% - 3.2%), P = .001), E/e' was rendered nonsignificant for long-term outcomes by multivariable adjustment (p = ns for both). LVEF, on the contrary, was a highly significant predictor in the adjusted long-term model. CONCLUSION: E/e' is associated with poor outcome in STEMI, but LVEF is a stronger predictor of long-term risk.

Hair growth potential of Salvia plebeia extract and its associated mechanisms.

Context: Although Salvia plebeia (SP) R. Brown (Labiatae) is known to possess various biological activities, the effects of SP on hair growth have not been elucidated.Objective: To investigate the hair growth potential of SP extract by using human dermal papilla cells (hDPCs) and C57BL/6 mice.Materials and methods: The entire SP plant sample was ground into powder and extracted with 99.9% methyl alcohol. Various concentrations of SP extract were added to hDPCs to evaluate the proliferation, migration, and factors related to hair growth and cycling. Effect of topical SP administration on hair regrowth was tested in vivo in male C57BL/6 mice for 21 days.Results: SP extract significantly increased the proliferation of cultured hDPCs at doses of 15.6 and 31.3 µg/mL compared to control group by 123% and 132%, respectively. Expression of hepatocyte growth factor increased while the level of TGF-ß1 and SMAD2/3 decreased when treated with SP extract. At the molecular level, the extract activated Wnt/ß-catenin signalling by raising ß-catenin and phospho-GSK3ß expression. SP extract also exerted anti-apoptotic and proliferative effects in hDPCs by increasing the Bcl-2/Bax ratio and activating cell proliferation-related proteins, ERK and Akt. Finally, the extract caused an induction of the anagen phase leading to significantly enhanced hair growth in treated male mice.Discussion and conclusion: Our results indicate that SP extract has the capacity to activate hDPCs into a proliferative state to promote hair growth. Further research is necessary to determine the bioactive components and their mechanisms of action responsible for SP-related hair growth effect.

Heart Failure With Preserved Ejection Fraction in the Young.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF), traditionally considered a disease of the elderly, may also affect younger patients. However, little is known about HFpEF in the young. METHODS: We prospectively enrolled 1203 patients with HFpEF (left ventricular ejection fraction ≥50%) from 11 Asian regions. We grouped HFpEF patients into very young (<55 years of age; n=157), young (55-64 years of age; n=284), older (65-74 years of age; n=355), and elderly (≥75 years of age; n=407) and compared clinical and echocardiographic characteristics, quality of life, and outcomes across age groups and between very young individuals with HFpEF and age- and sex-matched control subjects without heart failure. RESULTS: Thirty-seven percent of our HFpEF population was <65 years of age. Younger age was associated with male preponderance and a higher prevalence of obesity (body mass index ≥30 kg/m2; 36% in very young HFpEF versus 16% in elderly) together with less renal impairment, atrial fibrillation, and hypertension (all P<0.001). Left ventricular filling pressures and prevalence of left ventricular hypertrophy were similar in very young and elderly HFpEF. Quality of life was better and death and heart failure hospitalization at 1 year occurred less frequently ( P<0.001) in the very young (7%) compared with elderly (21%) HFpEF. Compared with control subjects, very young HFpEF had a 3-fold higher death rate and twice the prevalence of hypertrophy. CONCLUSIONS: Young and very young patients with HFpEF display similar adverse cardiac remodeling compared with their older counterparts and very poor outcomes compared with control subjects without heart failure. Obesity may be a major driver of HFpEF in a high proportion of HFpEF in the young and very young.

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.

Prediction of Survival in Asian Patients Hospitalized With Heart Failure: Validation of the OPTIMIZE-HF Risk Score.

BACKGROUND: Risk scores predicting in-patient mortality in heart failure patients have not been designed specifically for Asian patients. We aimed to validate and recalibrate the OPTIMIZE-HF risk model for in-hospital mortality in a multiethnic Asian population hospitalized for heart failure. METHODS AND RESULTS: Data from the Singapore Cardiac Databank Heart Failure on patients admitted for heart failure from January 1, 2008, to December 31, 2013, were included. The primary outcome studied was in-hospital mortality. Two models were compared: the original OPTIMIZE-HF risk model and a modified OPTIMIZE-HF risk model (similar variables but with coefficients derived from our cohort). A total of 15,219 patients were included. The overall in-hospital mortality was 1.88% (n = 286). The original model had a C-statistic of 0.739 (95% CI 0.708-0.770) with a good match between predicted and observed mortality rates (Hosmer-Lemeshow statistic 13.8; P = .086). The modified model had a C-statistic of 0.741 (95% CI 0.709-0.773) but a significant difference between predicted and observed mortality rates (Hosmer-Lemeshow statistic 17.2; P = .029). The modified model tended to underestimate risk at the extremes (lowest and highest ends) of risk. CONCLUSIONS: We provide the first independent validation of the OPTIMIZE-HF risk score in an Asian population. This risk model has been shown to perform reliably in our Asian cohort and will potentially provide clinicians with a useful tool to identify high-risk heart failure patients for more intensive management.

Potential role of IL-37 in atherosclerosis.

IL-37 is a member of the IL-1 family, but unlike most other members of this family of cytokines, it has wide-ranging anti-inflammatory properties. Initially shown to bind IL-18 binding protein and prevent IL-18-mediated inflammation, its known role has been expanded to include distinct pathways, both intracellular involving the transcription factor Smad3, and extracellular via binding to the orphan receptor IL-1R8. A number of recent publications investigating the role of IL-37 in atherosclerosis and ischemic heart disease have revealed promising therapeutic value of the cytokine. Although research concerning the role of IL-37 and its mechanism in atherosclerosis is relatively scant, there are a number of well-known atherosclerotic processes that this cytokine can mediate with the potential of modulating the disease progression itself. This review will probe in detail the effects of IL-37 on important pathological processes such as inflammation, dysregulated lipid metabolism, and apoptosis, by analyzing existing data as well as exploring the potential of this cytokine to influence these properties.

Management of patients with diabetes and heart failure with reduced ejection fraction: An international comparison.

AIMS: To compare the management of patients with diabetes and heart failure with reduced ejection fraction (HFrEF) in the United States and Asia to understand variations in treatment patterns across different healthcare systems. MATERIALS AND METHODS: Our cohort included patients with diabetes and HFrEF (ejection fraction <40%) from a US-based registry of adults with diabetes (2013-2016, electronic health records) and a multi-national Asian registry of adults with heart failure (2010-2016, prospective registry). Asian countries were categorized as high income (HI) or low income (LI), according to the United Nations classification. Rates of use of guideline-directed medical therapies (determined through review of active medication lists) were compared across regions. RESULTS: Patients with diabetes and HFrEF in the United States (n = 28 877) were older, had higher body mass indices, and were more likely to have coronary disease than those in Asia (n = 2235). Compared with US patients, the use of guideline-directed medical therapy for HFrEF was lower in patients in LI Asian countries (angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers: patients in the United States, 77% vs. patients in HI Asian countries, 76% vs patients in LI Asian countries, 69%; ß-blockers: patients in the United States, 91% vs. patients in HI Asian countries, 87% vs. patients in LI Asian countries, 69%; P < 0.001 for both). Insulin was used more commonly in the United States (44% vs. 24% vs. 25%, respectively; P < 0.001), whereas sulphonylureas were more often prescribed in Asian countries (42% vs. 52% vs. 54%; respectively, P < 0.001). Thiazolidinediones were prescribed in 6% of US patients compared with <1% of patients in Asia. The use of newer diabetes medications was <5% in all. CONCLUSION: In both the United States and Asia, opportunities for improvement in the use of evidence-based therapies exist for patients with both diabetes and HFrEF. Effective tools to guide medication choices for these complex, high-risk patients could have substantial impact on quality and outcomes.

Harnessing technology and molecular analysis to understand the development of cardiovascular diseases in Asia: a prospective cohort study (SingHEART).

BACKGROUND: Cardiovascular disease (CVD) imposes much mortality and morbidity worldwide. The use of "deep learning", advancements in genomics, metabolomics, proteomics and devices like wearables have the potential to unearth new insights in the field of cardiology. Currently, in Asia, there are no studies that combine the use of conventional clinical information with these advanced technologies. We aim to harness these new technologies to understand the development of cardiovascular disease in Asia. METHODS: Singapore is a multi-ethnic country in Asia with well-represented diverse ethnicities including Chinese, Malays and Indians. The SingHEART study is the first technology driven multi-ethnic prospective population-based study of healthy Asians. Healthy male and female subjects aged 21-69 years old without any prior cardiovascular disease or diabetes mellitus will be recruited from the general population. All subjects are consented to undergo a detailed on-line questionnaire, basic blood investigations, resting and continuous electrocardiogram and blood pressure monitoring, activity and sleep tracking, calcium score, cardiac magnetic resonance imaging, whole genome sequencing and lipidomic analysis. Outcomes studied will include mortality and cause of mortality, myocardial infarction, stroke, malignancy, heart failure, and the development of co-morbidities. DISCUSSION: An initial target of 2500 patients has been set. From October 2015 to May 2017, an initial 683 subjects have been recruited and have completed the initial work-up the SingHEART project is the first contemporary population-based study in Asia that will include whole genome sequencing and deep phenotyping: including advanced imaging and wearable data, to better understand the development of cardiovascular disease across different ethnic groups in Asia.