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Transdermal nicotine patches (TNPs), administering nicotine into the bloodstream through skin, have been widely used as nicotine replacement therapy, and exposure to nicotine can be detected by measurement of plasma cotinine concentration. In animal studies, nicotine treatment could increase the number of endothelial progenitor cells (EPCs), but the effect of TNPs on circulating EPCs and their activity in humans remained unclear. This study aimed to explore the influence of TNPs on circulating EPCs with surface markers of CD34, CD133, and/or KDR, and colony‐forming function plus migration activity of early EPCs derived from cultured peripheral blood mononuclear cells before and after TNP treatments in young healthy nonsmokers. In parallel, pulse wave analysis (PWA) was applied to evaluate the vascular effect of TNP treatments. Twenty‐one participants (25.8 ± 3.6 years old, 10 males) used TNP (nicotine: 4.2 mg/day) for 7 consecutive days. During the treatment, the CD34+ EPCs progressively increased in number. In addition, the number of EPCs positive for CD34/KDR, CD133, and CD34/CD133 were also increased on day 7 of the treatment. Furthermore, the early EPC colony‐forming function and migration activity were increased with the plasma cotinine level positively correlating with change in colony‐forming unit number. PWA analyses on day 7, compared with pretreatment, did not show significant change except diastolic pressure time index, which was prolonged and implied potential vascular benefit. In conclusion, 7‐day TNP treatments could be a practical strategy to enhance angiogenesis of circulating EPCs to alleviate tissue ischemia without any hemodynamic concern. [ABSTRACT FROM AUTHOR]

This research explores the role of microRNA in senescence of human endothelial progenitor cells (EPCs) induced by replication. Hsa‐miR‐134‐5p was found up‐regulated in senescent EPCs where overexpression improved angiogenic activity. Hsa‐miR‐134‐5p, which targeted transforming growth factor β‐activated kinase 1‐binding protein 1 (TAB1) gene, down‐regulated TAB1 protein, and inhibited phosphorylation of p38 mitogen‐activated protein kinase (p38) in hsa‐miR‐134‐5p‐overexpressed senescent EPCs. Treatment with siRNA specific to TAB1 (TAB1si) down‐regulated TAB1 protein and subsequently inhibited p38 activation in senescent EPCs. Treatment with TAB1si and p38 inhibitor, respectively, showed angiogenic improvement. In parallel, transforming growth factor Beta 1 (TGF‐β1) was down‐regulated in hsa‐miR‐134‐5p‐overexpressed senescent EPCs and addition of TGF‐β1 suppressed the angiogenic improvement. Analysis of peripheral blood mononuclear cells (PBMCs) disclosed expression levels of hsa‐miR‐134‐5p altered in adult life, reaching a peak before 65 years, and then falling in advanced age. Calculation of the Framingham risk score showed the score inversely correlates with the hsa‐miR‐134‐5p expression level. In summary, hsa‐miR‐134‐5p is involved in the regulation of senescence‐related change of angiogenic activity via TAB1‐p38 signalling and via TGF‐β1 reduction. Hsa‐miR‐134‐5p has a potential cellular rejuvenation effect in human senescent EPCs. Detection of human PBMC‐derived hsa‐miR‐134‐5p predicts cardiovascular risk. [ABSTRACT FROM AUTHOR]

This study explores the impact of senescence on autocrine C‐C motif chemokine ligand 5 (CCL5) in human endothelial progenitor cell (EPCs), addressing the poorly understood decline in number and function of EPCs during ageing. We examined the effects of replication‐induced senescence on CCL5/CCL5 receptor (CCR5) signalling and angiogenic activity of EPCs in vitro and in vivo. We also explored microRNAs controlling CCL5 secretion in senescent EPCs, its impact on EPC angiogenic activity, and validated our findings in humans. CCL5 secretion and CCR5 levels in senescent EPCs were reduced, leading to attenuated angiogenic activity. CCL5 enhanced EPC proliferation via the CCR5/AKT/P70S6K axis and increased vascular endothelial growth factor (VEGF) secretion. Up‐regulation of miR‐409 in senescent EPCs resulted in decreased CCL5 secretion, inhibiting the angiogenic activity, though these negative effects were counteracted by the addition of CCL5 and VEGF. In a mouse hind limb ischemia model, CCL5 improved the angiogenic activity of senescent EPCs. Analysis involving 62 healthy donors revealed a negative association between CCL5 levels, age and Framingham Risk Score. These findings propose CCL5 as a potential biomarker for detection of EPC senescence and cardiovascular risk assessment, suggesting its therapeutic potential for age‐related cardiovascular disorders. [ABSTRACT FROM AUTHOR]

We explored the roles of hsa‐microRNA (miR)‐409‐3p in senescence and signalling mechanism of human endothelial progenitor cells (EPCs). Hsa‐miR‐409‐3p was found upregulated in senescent EPCs. Overexpression of miRNA mimics in young EPCs inhibited angiogenesis. In senescent EPCs, compared to young EPCs, protein phosphatase 2A (PP2A) was downregulated, with activation of p38/JNK by phosphorylation. Young EPCs treated with siPP2A caused inhibited angiogenesis with activation of p38/JNK, similar to findings in senescent EPCs. Time series analysis showed, in young EPCs treated with hsa‐miR‐409‐3p mimics, PP2A was steadily downregulated for 72 h, while p38/JNK was activated with a peak at 48 hours. The inhibited angiogenesis of young EPCs after miRNA‐409‐3p mimics treatment was reversed by the p38 inhibitor. The effect of hsa‐miR‐409‐3p on PP2A signalling was attenuated by exogenous VEGF. Analysis of human peripheral blood mononuclear cells (PBMCs) obtained from healthy people revealed hsa‐miR‐409‐3p expression was higher in those older than 65 years, compared to those younger than 30 years, regardless of gender. In summary, hsa‐miR‐409‐3p was upregulated in senescent EPCs and acted as a negative modulator of angiogenesis via targeting protein phosphatase 2 catalytic subunit alpha (PPP2CA) gene and regulating PP2A/p38 signalling. Data from human PBMCs suggested hsa‐miR‐409‐3p a potential biomarker for human ageing. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to investigate the functional correlate, clinical relevance, and prognostic implications of novel left ventricular (LV) deformations in patients with atrial fibrillation (AF). Methods and results: LV deformational indices, including peak global longitudinal strain (GLS), systolic strain rates (SRs), and early diastolic strain rates (SRe) were measured in a large‐scale AF population. We related such measures to key clinical heart failure (HF) markers, conventional echocardiographic ventricular parameters, and clinical outcomes. Among 1483 subjects with newly diagnosed AF (mean age, 71.6 ± 12.4 years; 55.5% male), worsened GLS (mean, − 12.6 ± 3.9%) and strain rates (SRs and SRe: mean, − 0.86 ± 0.27 and 1.25 ± 0.41 1/s, respectively) by our three‐beat measures were independently correlated with higher C‐reactive protein, N‐terminal pro‐B‐type natriuretic peptide, higher E/e′, more impaired LV ejection fraction (LVEF < 50%), lower estimated glomerular filtration rate, permanent AF, and prevalent HF (all P < 0.05). LV deformations by three‐beat analysis well correlated with the respective results of traditional methods. Abnormal GLS (>− 14.7%) was common in our cohort (67.8%) despite an averaged preserved LVEF (58.4 ± 14.2%), with worse GLS and SRe being associated with higher composite HF re‐admissions/death during the 2.9 year follow‐up (inter‐quartile range, 1.6–4.1 years) in multivariate models incorporating key LV indices (LVEF, LV mass index, and E/e′) (all P < 0.001). Sensitivity analysis by excluding those with regional wall motion abnormality showed broadly similar findings. An improved risk reclassification was observed when GLS and SRe were separately added to the LVEF. Comparison of the AF cohort with a fully matched independent non‐AF cohort at the same baseline LVEF level showed a substantially lower GLS [− 13.2 ± 3.8% (AF) vs. 18.1 ± 3.2% (non‐AF)] and higher clinical events rate (hazard ratio, 1.41 [95% confidence interval, 1.14–1.75]; log‐rank P = 0.002) in the AF cohort. Conclusions: Impaired LV function defined by myocardial deformation was common in patients with AF and provides independent prognostic values over conventional measures with improved risk prediction. Our data highlight the need for implementing cardiac deformations in daily practice for patients with AF. [ABSTRACT FROM AUTHOR]

Aims: Excessive visceral adiposity (VAT) plays an essential role in metabolic derangements with those close to heart further mediates myocardial homeostasis. The disparate biological links between region‐specific VAT and cardiometabolic profiles as mediators influencing atrial kinetics remain unexplored. Methods and results: Among 1326 asymptomatic individuals, region‐specific VAT including peri‐aortic root fat (PARF) and total pericardial fat (PCF) of cardiac region, together with thoracic peri‐aortic adipose tissue (TAT), was assessed using multiple‐detector computed tomography. VAT measures were related to functional left atrial (LA) metrics assessed by speckle‐tracking algorithm and clinical outcomes of atrial fibrillation (AF) and heart failure (HF). Multivariate linear regression models incorporating body fat, metabolic syndrome, and E/TDI‐e' consistently demonstrated independent associations of larger PARF/PCF with peak atrial longitudinal systolic strain (PALS) reduction, higher LA stiffness, and worsened strain rate components; instead, TAT was independently associated with cardiometabolic profiles. PARF rather than PCF or TAT conferred independent prognostic values for incident AF/HF by multivariate Cox regression (adjusted hazard ratio: 1.56, 95% confidence interval: 1.17–2.08, P = 0.002) during a median of 1790 days (interquartile range: 25th to 75th: 1440–1927 days) of follow‐up, with subjects categorized into worst PALS and largest VAT tertiles demonstrating highest events (all log‐rank P < 0.001). Mediation analysis showed that higher triglyceride and lower high‐density lipoproteins may serve as intermediary factors for effects between VAT and LA functional metrics, with lesser role by glucose level. Conclusions: Visceral adiposity surrounding atrial region was tightly associated with subclinical atrial dysfunction and incident AF or HF beyond metabolic factors. Instead, peri‐aortic adiposity may mediate their toxic effects mainly through circulating cardiometabolic profiles. [ABSTRACT FROM AUTHOR]

Aims: We aimed to investigate the functional alterations, diagnostic utilization, and prognostic implication of carotid arterial deformations in subjects with cardiovascular risk factors and heart failure (HF) with preserved ejection fraction (HFpEF). Methods and results: Among 251 prospectively participants (mean age 66.0 ± 9.8 years, 65.7% female) in a single centre between December 2011 and September 2014, carotid artery deformations including circumferential strain (CCS)/strain rate and radial strain were analysed by two‐dimensional speckle tracking. We further related these carotid artery deformation indices to HF biomarkers and cardiac structure and function by echocardiography and explored their prognostic values. Significant reductions of CCS, circumferential strain rate, and circumferential radial strain were observed across control (n = 52), high risk (n = 147), and HFpEF (n = 52) (trend P ≤ 0.001). Aging, hypertension, HFpEF, and higher pulse rate showed independent associations with reduced CCS by stepwise multivariate regressions (all P < 0.05). Higher CCS was inversely associated with better cardiac remodelling and functional indices, and lower multiple HF biomarkers (all P ≤ 0.005). After adjustment, higher CCS was independently associated with better global ventricular longitudinal strain/early diastolic strain rate, lower matrix metalloproteinase‐2, and N‐terminal propeptide of procollagen type III levels (adjusted coef: −0.08 and −19.9, all P < 0.05). During a median follow‐up of 1406 days (interquartile range: 1342‑1720 days), CCS less than 3.28% as a cut‐off had markedly higher HF events [Harrell's C: 0.72, adjusted HR: 2.20 (95% confidence interval: 1.24, 3.16), P = 0.008]. CCS also showed significantly improved risk prediction for HF over global ventricular longitudinal strain (net reclassification index: 48%, P = 0.001; integrated discrimination improvement: 1.8%, P < 0.001). Conclusions: Carotid artery deformations using two‐dimensional speckle‐tracking imaging showed novel mechanistic insights on functional arterial alterations reflecting coupled arterial‐ventricular pathophysiology. Utilization of such measure may further provide additive prognostic value to advanced myocardial functional assessment. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to evaluate the prognostic significance of nutritional status in post‐discharge Asians with heart failure with preserved ejection fraction (HFpEF). Methods and results: We examined the prognostic implications of body mass index (BMI) and nutritional markers among consecutive patients hospitalized for HFpEF. Nutritional metrics were estimated by serum albumin (SA), prognostic nutritional index (PNI), Controlling Nutritional Status (CONUT) score, and geriatric nutritional risk index. Among 1120 patients (mean age: 77.2 ± 12.6 years, 39.4% men), mean SA levels, PNI, CONUT scores, and geriatric nutritional risk index were 3.3 ± 0.6 g/dL, 40.2 ± 8.7, 5.5 ± 2.1, and 95.9 ± 14.5, respectively. Lean body size, higher white blood cell counts and C‐reactive protein levels, anaemia, and lack of angiotensin blocker use were independently associated with malnutrition (defined by SA < 3.5 g/dL). Higher SA levels [hazard ratio (HR): 0.67 (95% confidence interval, CI: 0.53–0.85)], higher PNI [HR: 0.97 (95% CI: 0.95–0.99)], and higher geriatric nutritional risk index [HR: 0.98 (95% CI: 0.97–0.99)] (all P < 0.05) were all associated with longer survival, with higher CONUT score [HR: 1.08 (95% CI: 1.02–1.13)] exhibited higher mortality in Cox regression models and with higher SA levels/PNI but not BMI further contributing to the reduced rate of re‐hospitalization (both P < 0.05). Categorizing BMI (25 kg/m2 as cut‐off) and nutritional status showed significantly higher mortality rates among patients with lower BMI/malnutrition than among those with BMI/better nutrition (SA level, PNI, and CONUT score, all P < 0.01). Restricted cubic spline regression revealed a marked survival benefit of better nutrition with increasing BMI (adjusted Pinteraction for both SA level and PNI: <0.001; adjusted Pinteraction for CONUT score: 0.046). Conclusions: Malnutrition was frequently and strongly associated with systemic inflammation in Asian patients hospitalized for acute HFpEF. Our findings also indicate that nutrition may play a pivotal role in metabolic protection in this population. [ABSTRACT FROM AUTHOR]

Aims: Left atrial (LA) remodelling is an important predictor of cardiovascular events of heart failure (HF) and atrial fibrillation. Data regarding diagnostic value of LA remodelling on diastolic dysfunction (DD) and preclinical HF remain largely unexplored. Methods and results: We assessed LA dimension (LAD) in 8368 consecutive asymptomatic Asians (mean age: 49.7, 38.9% women) and related such measure to updated American Society of Echocardiography (ASE) DD criteria and newly revised N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) cut‐off (≥125 pg/mL) and HF with preserved ejection fraction criteria incorporating NT‐proBNP and echocardiography parameters by the European Society of Cardiology (ESC). LAD and indexed LAD (LADi) were both inversely correlated with myocardial relaxation e′ and positively associated with indexed LA volume, left ventricular E/e′, and tricuspid regurgitation velocity (all P < 0.001) and showed significantly graded increase across ASE‐defined 'normal', 'inconclusive', and 'DD' categories (30.9, 34.4, and 36.5 mm; 16.7, 19.1, and 20.6 mm/m2, for LAD/LADi, both P for trend: <0.001, respectively). Substantial differences of LAD/LADi (31.3 vs. 33.6 mm/16.7 vs. 19.2 mm/m2, both P < 0.001) between ESC low and high HF probability using NT‐proBNP cut‐off were also observed. Multivariate linear and logistic models demonstrated that LAD set at 34 mm was independently associated with ASE‐defined diastolic indices, DD existence, and elevated NT‐proBNP (all P < 0.05). The use of LAD further yielded high diagnostic accuracy in DD (area under receiving operative characteristic curve: 0.77, 95% confidence interval [0.73, 0.80]; negative predictive value: 97.9%) and in ESC‐recommended HF with preserved ejection fraction criteria (area under receiving operative characteristic curve: 0.70, 95% confidence interval [0.65, 0.75]; negative predictive value: 98.7%) with high predictive value in LA remodelling (>34 mL/m2; positive predictive value: 96%) and well‐discriminated ESC‐recommended NT‐proBNP (≥125 pg/mL, LAD: 37 mm) for HF. Conclusions: Single utilization of atrial remodelling is highly useful for ruling out presence of DD and provides practical threshold for identifying preclinical HF based on most updated guidelines. [ABSTRACT FROM AUTHOR]

This article discusses a study which determined the functional attributes of CD4+CD25+ regulatory T cells in cancer progression by suppressing antitumor immunity. Researchers performed triple-color flow cytometry to study the phenotype expression of CD4+CD25+ regulatory T cells and CD8+ T cells in the peripheral blood lymphocytes. The findings and conclusions of the study are explored.

Background. To study if there are specific problems in laparoscopically assisted vaginal hysterectomy (LAVH) for a certain weight of bulky uteri and the strategies to overcome such problems. Methods. One hundred and eighty-one women with myoma or adenomyosis, weighing 350-1,590 g, underwent LAVH between August 2002 and December 2005. Key surgical strategies were special sites for trocar insertion, uterine artery or adnexal collateral pre-ligation, laparoscopic and transvaginal volume reduction technique. The basic clinical and operative parameters were recorded for analysis. Results. Based on significant differences in the operative time and estimated blood loss, the patients were divided into medium uteri weighing 350-749 g, n=138 (76%), and large uteri weighing ≥750 g, n=43 (24%). There was no significant difference in terms of age, body mass index, preoperative diagnoses, complications and duration of hospital stay among groups. The operative time and estimated blood loss increased with larger uterine size (p<0.001). The operative time (196±53, 115-395 min), estimated blood loss (234±200, 50-1,000 ml) and frequency of excessive bleeding (14%) or transfusion (5%) were significantly greater, but in acceptable ranges, for those with large uteri. Conversion to laparotomy was required in a patient (2%) with a large uterus, and the overall conversion rate was 0.6%. There was no re-operation or surgical mortality. Conclusion. Using various combinations of special strategies, most experienced gynecologic surgeons can conduct LAVH for most large uteri with minimal rates of complications and conversion to laparotomy. [ABSTRACT FROM AUTHOR]

Aim: To evaluate a strategy for successful laparoscopic-assisted vaginal hysterectomy (LAVH) in patients with extensive pelvic adhesion. Methods: Two hundred and thirty-six patients who underwent LAVH at National Taiwan University Hospital were retrospectively enrolled. Twenty-three patients (9.7%) had unexpected extensive pelvic adhesions. A special procedure of uterine artery preligation through retroperitoneal downstream ureter tracking was applied to overcome this problem. The clinical characteristics of the study group were analysed. The operative parameters and the outcome were compared between those with and without extensive pelvic adhesions. Results: Having extensive adhesions, 17 patients were associated with endometriosis and the other six were secondary to previous Caesarean delivery or pelvic inflammation. The cul-de-sac was partially and totally obliterated in 10 and 13 patients, respectively. These 23 patients had longer operation time (184 vs 146 min, P < 0.05), more blood loss (146 vs 89 mL, P < 0.05), but smaller extirpated uteri (278 vs 372 g, P = 0.063), compared with the other 213 patients. The average hospital stay was comparable (3.2 vs 3.4 days) and there were no ureteral injuries or excessive bleeding. Most importantly, not a single case was converted to laparotomy. Conclusion: Pelvic adhesions of various underlying diseases are associated with increased complication and conversion rates during LAVH. Although this technique is not new, we believe that the special procedure of uterine artery preligation through retroperitoneal downstream ureter tracking may provide a safe approach for general gynecologists to complete successful LAVH in patients with unexpected extensive pelvic adhesions. [ABSTRACT FROM AUTHOR]

It is presently the right time for clarifying human papillomavirus (HPV)-associated cellular immunity and clinical implications before global HPV vaccination programs begin. Infection with oncogenic HPV associates with the progression of cervical neoplasia. Both cellular and humoral immune responses are essential for the clearance of HPV-associated cervical lesions. There is increasing evidence that the immune system plays a pivotal role in determining the outcome of HPV infection. Viruses and associated neoplastic cells are proposed to have evolved mechanisms to avoid immune attack. T-cell-mediated immune responses against oncogenic HPV are believed to play a central role in cervical carcinogenesis. The presence of HPV-specific cytotoxic T lymphocytes (CTL) in a majority of human cervical cancer patients provides an approach for further study of their functional role in modulating this malignancy. Tumor-infiltrating lymphocytes (TIL) develop as manifestations of the recognition and defense against malignant cells by the host immune system. Cancer cells may overcome immune surveillance, either by downregulating the proliferation of HPV-specific CTL, or altering the effector compositions of immune cells against HPV infections. TIL in the tumor microenvironment can be functionally inhibited and lose the ability of clonal proliferation as a result of depressed expression of IL-2Rα. The upregulation of inhibitory signaling relates to the modulation of the virus- and/or tumor-specific immune responses. Alteration of host genetic susceptibility may also lead to abnormal immune response as a general genomic instability resulting from virus persistence. Induction of HPV-specific immune responses is anticipated as an intimate point for the treatment of cervical neoplasia. [ABSTRACT FROM AUTHOR]

Background. Pelvic organ prolapse is a common problem in women and often requires surgical management. Sacrospinous colpopexy (SSC) requires significant expertise, especially in placement of the suture into sacrospinous ligament (SSL). Methods. Veronikis ligature carrier (VLC) designed for SSC was used to facilitate suture placement and retrieval under direct visualization within the confines of the pararectal space. From December 2003 through March 2004, SSC was performed in 20 patients with VLC as part of their site-specific reconstructive pelvic surgery (group A). The historic control group (group B) included 15 patients who underwent SSC with a straight needle holder between March 1999 and March 2001. Results. There was no significant difference in age, gravity, parity, body mass index, blood loss, and hospital stay in both groups with the diagnosis of uterovaginal prolapse or posthysterectomy vaginal vault prolapse. The median operation time for group A and group B was 35min (range 25–40min) and 75min (range 45–128min), respectively (P <0.001). It took less than 5min to introduce two sutures through the SSL by VLC in group A but 20–40 min by straight needle holder in group B. There was no injury to the bladder, rectum, pudendal nerve, or major pelvic vessels. Conclusions. VLC allows rapid and safe introduction of the suspending suture through the SSL and makes SSC easy to perform. [ABSTRACT FROM AUTHOR]

To determine the influence of hyaluronan and its receptor CD44 in the angiogenesis and invasiveness of intravenous leiomyomatosis (IVL).Paraffin-embedded sections from four IVL cases and 10 uterine leiomyoma cases were immunohistochemically stained for CD34, CD44, basic fibroblast growth factor (bFGF), vascular endothelial growth factor, and platelet-derived growth factor and assayed for microvessel densities. Hyaluronan was immunostained by biotinylated hyaluronan-binding peptide and the results were clinically correlated.CD34 labeling showed significantly increased microvessel counts in IVL (156.6 ± 3.7), when compared to uterine leiomyomas (61.3 ± 27.3;P < 0.001). Hyaluronan and its receptor CD44 were prominently expressed in IVL when compared to leiomyomas and associated with an elevation in bFGF expression.IVL is a highly vascular neoplasm with elevated microvessel counts. The increase of hyaluronan and CD44 expression in IVL suggests that it is highly angiogenic and has an invasive potential. Elevation of hyaluronan may play a possible role in the pathogenesis of IVL. [ABSTRACT FROM AUTHOR]

The article presents a case report of a 35- year old woman who had a small bowel volvulus caused by re-implantation and growth of remnant tissue from a removal of ovarian mucinous cystadenoma by laparoscopy. It determined that good surgical technique and adequate care should be applied to minimize the risk of more serious complications.

Presents a case of pure primary ovarian squamous cell carcinoma with FIGO (International Federation of Gynecology and Obstetrics) stage IV, grade III in a 63-year-old woman. Treatment of the patient with paclitaxel and cisplatin after optimal debulking surgery; Response of the patient to the postoperative adjuvant chemotherapy; Rapid progression of the disease 7 months subsequent to surgery at the time of follow-up.

Background The angiotensin receptor-neprilysin inhibitor (LCZ696) has emerged as a promising pharmacological intervention against renin-angiotensin system inhibitor in reduced ejection fraction heart failure (HFrEF). Whether the therapeutic benefits may vary among heterogeneous HFrEF subgroups remains unknown. Methods and Results This study comprised a pooled 2-center analysis including 1103 patients with symptomatic HFrEF with LCZ696 use and another 1103 independent HFrEF control cohort (with renin-angiotensin system inhibitor use) matched for age, sex, left ventricular ejection fraction, and comorbidity conditions. Three main distinct phenogroup clusterings were identified from unsupervised machine learning using 29 clinical variables: phenogroup 1 (youngest, relatively lower diabetes prevalence, highest glomerular filtration rate with largest left ventricular size and left ventricular wall stress); phenogroup 2 (oldest, lean, highest diabetes and vascular diseases prevalence, lowest highest glomerular filtration rate with smallest left ventricular size and mass), and phenogroup 3 (lowest clinical comorbidity with largest left ventricular mass and highest hypertrophy prevalence). During the median 1.74-year follow-up, phenogroup assignment provided improved prognostic discrimination beyond Meta-Analysis Global Group in Chronic Heart Failure risk score risk score (all net reclassification index P <0.05) with overall good calibrations. While phenogroup 1 showed overall best clinical outcomes, phenogroup 2 demonstrated highest cardiovascular death and worst renal end point, with phenogroup 3 having the highest all-cause death rate and HF hospitalization among groups, respectively. These findings were broadly consistent when compared with the renin-angiotensin system inhibitor control as reference group. Conclusions Phenomapping provided novel insights on unique characteristics and cardiac features among patients with HFrEF with sacubitril/valsartan treatment. These findings further showed potentiality in identifying potential sacubitril/valsartan responders and nonresponders with improved outcome discrimination among patients with HFrEF beyond clinical scoring.

Background Fragmented QRS (fQRS) morphology as a surrogate marker of the possible presence of myocardial scarring has been shown to confer a higher risk in patients with reduced ejection fraction heart failure. We aimed to investigate the pathophysiological correlates and prognostic implications of fQRS in patients with heart failure with preserved ejection fraction (HFpEF). Methods and Results We consecutively studied 960 patients with HFpEF (76.4±12.7 years, men: 37.2%). fQRS was assessed using a body surface ECG during hospitalization. QRS morphology was available and classified into 3 categories among 960 subjects with HFpEF as non-fQRS, inferior fQRS, and anterior/lateral fQRS groups. Despite comparable clinical features in most baseline demographics among the 3 fQRS categories, anterior/lateral fQRS showed significantly higher B-type natriuretic peptide/troponin levels (both P <0.001), with both the inferior and anterior/lateral fQRS HFpEF groups demonstrating a higher degree of unfavorable cardiac remodeling, greater extent of myocardial perfusion defect, and slower coronary flow phenomenon (all P <0.05). Patients with anterior/lateral fQRS HFpEF exhibited significantly altered cardiac structure/function and more impaired diastolic indices (all P <0.05). During a median of 657 days follow-up, the presence of anterior/lateral fQRS conferred a doubled HF re-admission risk (adjusted hazard ratio 1.90, P <0.001), with both inferior and anterior/lateral fQRS having a higher risk of cardiovascular and all-cause death (all P <0.05) by using Cox regression models. Conclusions The presence of fQRS in HFpEF was associated with more extensive myocardial perfusion defects and worsened mechanics, which possibly denotes a more severe involvement of cardiac damage. Early recognition in such patients with HFpEF likely benefits from targeted therapeutic interventions.

Background Visceral adipose tissue is assumed to be an important indicator for insulin resistance and diabetes beyond overweight/obesity. We hypothesized that region-specific visceral adipose tissue may regulate differential biological effects for new-onset diabetes regardless of overall obesity. Methods and Results We quantified various visceral adipose tissue measures, including epicardial adipose tissue, paracardial adipose tissue, interatrial fat, periaortic fat, and thoracic aortic adipose tissue in 1039 consecutive asymptomatic participants who underwent multidetector computed tomography. We explored the associations of visceral adipose tissue with baseline dysglycemic indices and new-onset diabetes. Epicardial adipose tissue, paracardial adipose tissue, interatrial fat, periaortic fat, and thoracic aortic adipose tissue were differentially and independently associated with dysglycemic indices (fasting glucose, postprandial glucose, HbA1c, and homeostasis model assessment of insulin resistance) beyond anthropometric measures. The superimposition of interatrial fat and thoracic aortic adipose tissue on age, sex, body mass index, and baseline homeostasis model assessment of insulin resistance expanded the likelihood of baseline diabetes (from 67.2 to 86.0 and 64.4 to 70.8, P for ∆ ꭕ 2 : <0.001 and 0.011, respectively). Compared with the first tertile, the highest interatrial fat tertile showed a nearly doubled risk for new-onset diabetes (hazard ratio, 2.09 [95% CI, 1.38-3.15], P <0.001) after adjusting for Chinese Visceral Adiposity Index. Conclusions Region-specific visceral adiposity may not perform equally in discriminating baseline dysglycemia or diabetes, and showed differential predictive performance in new-onset diabetes. Our data suggested that interatrial fat may serve as a potential marker for new-onset diabetes.