Prognostic superiority of global longitudinal strain beyond four-tiered ventricular hypertrophy in asymptomatic individuals.

BACKGROUND: This study aims to explore the clinical correlates of myocardial deformations using speckle-tracking algorithm and to determine the prognostic utility of such measures in asymptomatic ethnic Chinese population. METHODS: Global longitudinal (GLS), circumferential strain (GCS), and torsion were analyzed using featured tissue-tracking algorithm among 4049 symptom-free ethnic Chinese population. Hypertrophy (LVH) was classified into 4 tiers: indeterminate, dilated, thick and thick/dilated, by gender-stratified partition of end-diastolic volume index (EDVi) and LV mass/EDV0.67. RESULTS: LVH (7.3%) showed substantially lower GLS (-20.3 ± 1.82% vs. -18.9 ± 2.08%) yet higher torsion (2.20 ± 0.90 vs. 2.39 ± 1.01, p < 0.001) than non-LVH participants. Those with thick LVH (n = 123) were more obese, had higher blood pressure and increased high-sensitivity C-reactive protein (hs-CRP); with dilated/thick LVH (n = 26) group demonstrating highest pro-brain natriuretic peptide (NT-proBNP) and worse GLS compared to indeterminate-/non-LVH groups. There were independent associations among larger EDVi, higher NT-proBNP and decreased torsion, and among greater LV mass/EDV0.67, worse GLS, greater GCS/torsion and hs-CRP. Over a median of 2.3 years (IQR: 1.2-4.8), the dilated, thick, and dilated/thick LVH categorizations were associated with higher risk of composite all-cause death and heart failure (HF) compared to non-LVH (adjusted hazard ratio [HR]: 3.65, 3.72, 6.01, respectively, all p < 0.05). Per 1% GLS reduction was independently associated with higher risk (adjusted HR: 1.31, p < 0.001) and improved risk prediction (p ≤ 0.001 by integrated discrimination improvement [IDI]: 3.5%, 95% CI: 1.5%-5.6%, and continuous net reclassification improvement [NRI]: 42.3%, 95% CI: 24.0%-60.6%) over LVH. CONCLUSION: GLS improved risk stratification of four-tiered classification of LVH in asymptomatic ethnic Chinese.

Associations of obesity and malnutrition with cardiac remodeling and cardiovascular outcomes in Asian adults: A cohort study.

BACKGROUND: Obesity, a known risk factor for cardiovascular disease and heart failure (HF), is associated with adverse cardiac remodeling in the general population. Little is known about how nutritional status modifies the relationship between obesity and outcomes. We aimed to investigate the association of obesity and nutritional status with clinical characteristics, echocardiographic changes, and clinical outcomes in the general community. METHODS AND FINDINGS: We examined 5,300 consecutive asymptomatic Asian participants who were prospectively recruited in a cardiovascular health screening program (mean age 49.6 ± 11.4 years, 64.8% male) between June 2009 to December 2012. Clinical and echocardiographic characteristics were described in participants, stratified by combined subgroups of obesity and nutritional status. Obesity was indexed by body mass index (BMI) (low, ≤25 kg/m2 [lean]; high, >25 kg/m2 [obese]) (WHO-recommended Asian cutoffs). Nutritional status was defined primarily by serum albumin (SA) concentration (low, <45 g/L [malnourished]; high, ≥45 g/L [well-nourished]), and secondarily by the prognostic nutritional index (PNI) and Global Leadership Initiative on Malnutrition (GLIM) criteria. Cox proportional hazard models were used to examine a 1-year composite outcome of hospitalization for HF or all-cause mortality while adjusting for age, sex, and other clinical confounders. Our community-based cohort consisted of 2,096 (39.0%) lean-well-nourished (low BMI, high SA), 1,369 (25.8%) obese-well-nourished (high BMI, high SA), 1,154 (21.8%) lean-malnourished (low BMI, low SA), and 681 (12.8%) obese-malnourished (high BMI, low SA) individuals. Obese-malnourished participants were on average older (54.5 ± 11.4 years) and more often women (41%), with a higher mean waist circumference (91.7 ± 8.8 cm), the highest percentage of body fat (32%), and the highest prevalence of hypertension (32%), diabetes (12%), and history of cardiovascular disease (11%), compared to all other subgroups (all p < 0.001). N-terminal pro B-type natriuretic peptide (NT-proBNP) levels were substantially increased in the malnourished (versus well-nourished) groups, to a similar extent in lean (70.7 ± 177.3 versus 36.8 ± 40.4 pg/mL) and obese (73.1 ± 216.8 versus 33.2 ± 40.8 pg/mL) (p < 0.001 in both) participants. The obese-malnourished (high BMI, low SA) group also had greater left ventricular remodeling (left ventricular mass index, 44.2 ± 1.52 versus 33.8 ± 8.28 gm/m2; relative wall thickness 0.39 ± 0.05 versus 0.38 ± 0.06) and worse diastolic function (TDI-e' 7.97 ± 2.16 versus 9.87 ± 2.47 cm/s; E/e' 9.19 ± 3.01 versus 7.36 ± 2.31; left atrial volume index 19.5 ± 7.66 versus 14.9 ± 5.49 mL/m2) compared to the lean-well-nourished (low BMI, high SA) group, as well as all other subgroups (p < 0.001 for all). Over a median 3.6 years (interquartile range 2.5 to 4.8 years) of follow-up, the obese-malnourished group had the highest multivariable-adjusted risk of the composite outcome (hazard ratio [HR] 2.49, 95% CI 1.43 to 4.34, p = 0.001), followed by the lean-malnourished (HR 1.78, 95% CI 1.04 to 3.04, p = 0.034) and obese-well-nourished (HR 1.41, 95% CI 0.77 to 2.58, p = 0.27) groups (with lean-well-nourished group as reference). Results were similar when indexed by other anthropometric indices (waist circumference and body fat) and other measures of nutritional status (PNI and GLIM criteria). Potential selection bias and residual confounding were the main limitations of the study. CONCLUSIONS: In our cohort study among asymptomatic community-based adults in Taiwan, we found that obese individuals with poor nutritional status have the highest comorbidity burden, the most adverse cardiac remodeling, and the least favorable composite outcome.

Correction: Associations of obesity and malnutrition with cardiac remodeling and cardiovascular outcomes in Asian adults: A cohort study.

[This corrects the article DOI: 10.1371/journal.pmed.1003661.].

Sex, racial differences and healthy aging in normative reference ranges on diastolic function in Ethnic Asians: 2016 ASE guideline revisited.

BACKGROUND: Diastolic dysfunction (DD) has shown to be a hallmark pathological intermediate in the development of heart failure with preserved ejection fraction (HFpEF). We aim to establish age- and sex-stratified normal reference values of diastolic indices and to explore racial-differences. METHODS: We explored age- and sex-related structural/functional alterations from 6023 healthy ethnic Asians (47.1 ± 10.9 years, 61.3% men) according to 2016 American Society of Echocardiography (ASE) diastolic dysfunction (DD) criteria. Racial comparisons were made using data from London Life Sciences Prospective Population (LOLIPOP) study. RESULTS: Age- and sex-based normative ranges (including mean, median, 10% and 90% lower and upper reference values) were extracted from our large healthy population. In fully adjusted models, advanced age was independently associated with cardiac structural remodeling and worsened diastolic parameters including larger indexed LA volume (LAVi), lower e', higher E/e', and higher TR velocity; all p < 0.001), which were more prominent in women (P interaction: <0.05). Broadly, markedly lower e', higher E/e' and smaller LAVi were observed in ethnic Asians compared to Whites. DD defined by 2016 ASE criteria, despite at low prevalence (0.42%) in current healthy population, increased drastically with advanced age and performed perfectly in excluding abnormal NT-proBNP (≥125 pg/mL) (Specificity: 99.8%, NPV: 97.6%). CONCLUSION: This is to date the largest cohort exploring the normative reference values using guideline-centered diastolic parameters from healthy Asians, with aging played as central role in diastolic dysfunction. Our observed sex and ethnic differences in defining healthy diastolic cut-offs likely impact future clinical definition for DD in Asians.

The association among MDCT-derived three-dimensional visceral adiposities on cardiac diastology and dyssynchrony in asymptomatic population.

BACKGROUND: Visceral adipose tissue, a biologically active fat depot, has been proposed as a reliable marker for visceral adiposity and metabolic abnormalities. Effects of such adiposity on LV diastolic function and dyssynchrony remained largely unknown. METHODS: We assessed pericardial fat (PCF) and thoracic peri-aortic fat (TPAF) by three-dimensional (3D) volume-vender multi-detector computed tomography (MDCT) (Aquarius 3D Workstation, TeraRecon, San Mateo, CA, USA). Echo-derived diastolic parameters and tissue Doppler imaging (TDI) defined mitral annular systolic (S'), early diastolic (E') velocities as well as LV filling (E/E') were all obtained. Intra-ventricular systolic (Sys-D) and diastolic (Dias-D) dyssynchrony were assessed by TDI method. RESULTS: A total of 318 asymptomatic subjects (mean age: 53.5 years, 36.8 % female) were eligible in this study. Greater PCF and TPAF were both associated with unfavorable diastolic indices and higher diastolic dyssynchrony (all p < 0.05). These associations remained relatively unchanged in multi-variate models. PCF and TPAF set at 81.68 & 8.11 ml yielded the largest sensitivity and specificity (78.6 and 60 % for PCF, 75 and 66.6 % for TPAF, respectively) in predicting abnormally high LV diastolic dyssynchrony, which was defined as Dias-D≧55 ms. CONCLUSION: Increasing visceral adiposity may be associated with adverse effects on myocardium, primarily featured by worse diastolic function and greater degree of dyssynchrony.

Preclinical systolic dysfunction relating to ankle-brachial index among high-risk PAD population with preserved left ventricular ejection fraction.

Peripheral artery disease (PAD) shares common clinical risk factors, for example, endothelial dysfunction, with preserved ejection fraction (LVEF) heart failure (HFpEF). Whether PAD is associated with preclinical systolic dysfunction and higher HF risk among individuals presenting preserved LVEF remains uncertain. We retrospectively included outpatients with at least one known or established cardiovascular (CV) risk factor with LVEF ≥ 50%. Patients were categorized into high risk and low risk of developing PAD (PAD vs Non-PAD) by ankle-brachial index (ABI) (≤ 0.90 or > 1.4) and further stratified based on their history of HFpEF (HFpEF vs. Non-HFpEF), resulting in the formation of four distinct strata. Preclinical systolic dysfunction was defined using dedicated speckle-tracking algorithm. A total of 2130 consecutive patients were enrolled in the study, with a median follow-up of 4.4 years. The analysis revealed a higher prevalence of high risk of developing PAD in patients with HFpEF compared to those without HFpEF (25.1% vs. 9.4%). Both high risk of developing PAD and HFpEF were independently associated with preclinical systolic dysfunction (global longitudinal strain, GLS ≥ - 18%) (odds ratio, OR: 1.38; 95% confidence interval, CI: 1.03-1.86). In comparison to patients at low risk of developing PAD without HFpEF (Non-PAD/Non-HFpEF group), those categorized as having a high risk of developing PAD with HFpEF (PAD/HFpEF group) exhibited the most impaired GLS and a heightened susceptibility to heart failure hospitalization (hazard ratio, HR: 6.51; 95% CI: 4.43-9.55), a twofold increased risk of all-cause mortality (HR: 2.01; 95% CI: 1.17-3.38), cardiovascular mortality (HR: 2.44; 95% CI: 1.08-5.51), and non-cardiovascular mortality (HR: 1.78; 95% CI: 0.82-3.84). A high risk of developing PAD was strongly linked to impaired preclinical systolic function and an increased likelihood for subsequent hospitalization for HF, all-cause mortality, CV mortality and non-CV mortality. There is a clear need for preventive strategies aimed at reducing hospitalizations for HF and mortality in this high-risk population.

Relation of early-stage renal insufficiency and cardiac structure and function in a large population of asymptomatic Asians: a cross-sectional cohort analysis.

Background: Few studies have addressed early-stage kidney disease and preclinical cardiac structural and functional abnormalities from a large-scale Asian population. Further, the extent to which measures of myocardial function and whether these associations may vary by testing various formulas of renal insufficiency remains largely unexplored. Objective: To explore the associations among renal function, proteinuria, and left ventricular (LV) structural and diastolic functional alterations. Design: A cross-sectional, retrospective cohort study. Setting: Registered data from a cardiovascular health screening program at MacKay Memorial Hospital from June 2009 to December 2012. Participants: Asymptomatic individuals. Measurements: Renal function was evaluated in terms of estimated glomerular filtration rate (eGFR) by both MDRD and CKD-EPI formulas and severity of proteinuria, which were further related to cardiac structure, diastolic function (including LV e' by tissue Doppler), and circulating N-terminal pro-brain natriuretic peptide (NT-proBNP) level. Results: Among 4942 participants (65.8% men, mean age 49.4 ± 11.2 years), the mean CKD-EPI/MDRD eGFR was 90.6 ± 15.7 and 88.5 ± 16.9 ml/min/1.73m2, respectively. Lower eGFR, estimated either by the MDRD or CKD-EPI method, and higher proteinuria were significantly associated with lower LV e' and higher NT-proBNP (all p<0.05) even after adjusting for clinical covariates. In general, lower eGFR estimated by CKD-EPI and MDRD displayed similar impacts on worsening e' and NT-proBNP, rather than E/e', in multivariate models. Finally, lower LV e' or higher composite diastolic score, rather than E/e', demonstrated remarkable interaction with eGFR level estimated by either CKD-EPI or MDRD on circulating NT-proBNP level (p interaction <0.05). Limitations: Proteinuria was estimated using a urine dipstick rather than more accurately by the urine protein-to-creatinine ratio. Also, pertaining drug history and clinical hard outcomes were lacking. Conclusion: Both clinical estimate of renal insufficiency by eGFR or proteinuria, even in a relatively early clinical stage, were tightly linked to impaired cardiac diastolic relaxation and circulating NT-proBNP level. Elevation of NT-proBNP with worsening renal function may be influenced by impaired myocardial relaxation.

Penalized Model-Based Unsupervised Phenomapping Unravels Distinctive HFrEF Phenotypes With Improved Outcomes Discrimination From Sacubitril/Valsartan Treatment Independent of MAGGIC Score.

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.

Quantitative volumetric computed tomography embolic analysis, the Qanadli score, biomarkers, and clinical prognosis in patients with acute pulmonary embolism.

Detailed descriptions of acute pulmonary emboli (PE) morphology, total embolic volume (TEV), and their effects upon patients' clinical presentation and prognosis remain largely unexplored. We studied 201 subjects with acute PE to the emergency department of a single medical center from April 2009 to December 2014. Patient hemodynamics, Troponin I and D-dimer levels, echocardiography, and the 30-day, 90-day and long-term mortality were obtained. Contrast-enhanced computed tomography (CT) of pulmonary structures and 3-dimensional measures of embolic burden were performed. The results showed a linear association between the greater TEV and each of the following 4 variables (increasing incidence of right ventricular (RV) dysfunction, higher systolic pulmonary artery pressure (sPAP), greater RV diameter, and RV/left ventricular (LV) ratio (all p < 0.001)). Among the measures of CT and echocardiography, TEV and RV/LV ratio were significantly associated with impending shock. In backward stepwise logistic regression, TEV, age and respiratory rate remained independent associated with impending shock (OR: 1.58, 1.03, 1.18, respectively and all p < 0.005).Total embolic burden assessed by CT-based quantification serves as a useful index for stressed cardiopulmonary circulation condition and can provide insights into RV dysfunction and the prediction of impending shock.

Association of Non-Alcoholic Fatty Liver Disease and Hepatic Fibrosis with Epicardial Adipose Tissue Volume and Atrial Deformation Mechanics in a Large Asian Population Free from Clinical Heart Failure.

Non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease share several cardiometabolic risk factors. Excessive visceral fat can manifest as ectopic fat depots over vital organs, such as the heart and liver. This study assessed the associations of NAFLD and liver fibrosis with cardiac structural and functional disturbances. We assessed 2161 participants using ultrasound, and categorized them as per the NAFLD Fibrosis Score into three groups: (1) non-fatty liver; (2) fatty liver with low fibrosis score; and (3) fatty liver with high fibrosis score. Epicardial fat volume (EFV) was measured through multidetector computed tomography. All participants underwent echocardiographic study, including tissue Doppler-based E/e' ratio and speckle tracking-based left ventricular global longitudinal strain, peak atrial longitudinal strain (PALS), and atrial longitudinal strain rates during systolic, early and late-diastolic phases (ALSRsyst, ALSRearly. ALSRlate). Larger EFV, decreased e' velocity, PALS, ALSRsyst, and ALSRearly, along with elevated E/e' ratio, were seen in all groups, especially in those with high fibrosis scores. After multivariate adjustment for traditional risk factors and EFV, fibrosis scores remained significantly associated with elevated E/e' ratio, LA stiffness, and decreased PALS (ß: 0.06, 1.4, −0.01, all p < 0.05). Thus, NAFLD is associated with LV diastolic dysfunction and subclinical changes in LA contractile mechanics.

The association of pericardial fat and peri-aortic fat with severity of nonalcoholic fatty liver disease.

Visceral adipose tissue (VAT) is associated with central obesity, insulin resistance and metabolic syndrome. However, the association of body-site specific adiposity and non-alcoholic fatty liver disease (NAFLD) has not been well characterized. We studies 704 consecutive subjects who underwent annual health survey in Taiwan. All subjects have been divided into three groups including normal (341), mild (227) and moderate and severe (136) NAFLD according to ultrasound finding. Pericardial (PCF) and thoracic peri-aortic adipose tissue (TAT) burden was assessed using a non-contrast 16-slice multi-detector computed tomography (MDCT) dataset with off-line measurement (Aquarius 3DWorkstation, TeraRecon, SanMateo, CA, USA). We explored the relationship between PCF/TAT, NAFLD and cardiometabolic risk profiles. Patients with moderate and mild NAFLD have greater volume of PCF (100.7 ± 26.3vs. 77.1 ± 21.3 vs. 61.7 ± 21.6 ml, P < 0.001) and TAT (11.2 ± 4.1 vs. 7.6 ± 2.6 vs. 5.5 ± 2.6 ml, P < 0.001) when compared to the normal groups. Both PCF and TAT remained independently associated with NAFLD after counting for age, sex, triglyceride, cholesterol and other cardiometabolic risk factors. In addition, both PCF and TAT provided incremental prediction value for NAFLD diagnosis. (AUROC: 0.85 and 0.87, 95%, confidence interval: 0.82-0.89 and 0.84-0.90). Both visceral adipose tissues strongly correlated with the severity of NAFLD. Compared to PCF, TAT is more tightly associated with NAFLD diagnosis in a large Asian population.

Both epicardial and peri-aortic adipose tissue blunt heart rate recovery beyond body fat mass.

Background: Epicardial adipose tissue (EAT) as a marker of metabolic disorders has been shown to be closely associated with a variety of unfavorable cardiovascular events and cardiac arrhythmias. Data on regional-specific visceral adiposity outside the heart and its modulation on autonomic dysfunction, particularly heart rate recovery after exercise, remain obscure. Methods: We studied 156 consecutive subjects (mean age: 49.3 ± 8.0 years) who underwent annual health surveys and completed treadmill tests. Multi-detector computed tomography-based visceral adiposity, including EAT and peri-aortic fat (PAF) tissue, was quantified using dedicated software (Aquarius 3D Workstation, TeraRecon, San Mateo, CA, USA). We further correlated EAT and PAF with blood pressure and heart rate (HR) recovery information from an exercise treadmill test. Metabolic abnormalities were scored by anthropometrics in combination with biochemical data. Results: Increased EAT and PAF were both associated with a smaller reduction in systolic blood pressure during the hyperventilation stage before exercise compared to supine status (ß-coefficient (coef.): -0.19 and -0.23, respectively, both p < 0.05). Both visceral adipose tissue mediated an inverted relationship with heart rate recovery at 3 (EAT: ß-coef.: -0.3; PAF: ß-coef.: -0.36) and 6 min (EAT: ß-coef.: -0.32; PAF: ß-coef.: -0.34) after peak exercise, even after adjusting for baseline clinical variables and body fat composition (all p < 0.05). Conclusion: Excessive visceral adiposity, whether proximal or distal to the heart, may modulate the autonomic response by lowering the rate of HR recovery from exercise after accounting for clinical metabolic index. Cardiac autonomic dysfunction may partly explain the increase in cardiovascular morbidity and mortality related to both visceral fats.

Association of Female Menopause With Atrioventricular Mechanics and Outcomes.

Background: Despite known sex differences in cardiac structure and function, little is known about how menopause and estrogen associate with atrioventricular mechanics and outcomes. Objective: To study how, sex differences, loss of estrogen in menopause and duration of menopause, relate to atrioventricular mechanics and outcomes. Methods: Among 4051 asymptomatic adults (49.8 ± 10.8 years, 35%women), left ventricular (LV) and left atrial (LA) mechanics were assessed using speckle-tracking. Results: Post-menopausal (vs. pre-menopausal) women had similar LV ejection fraction but reduced GLS, reduced PALS, increased LA stiffness, higher LV sphericity and LV torsion (all p < 0.001). Multivariable analysis showed menopause to be associated with greater LV sphericity (0.02, 95%CI 0.01, 0.03), higher indexed LV mass (LVMi), lower mitral e', lower LV GLS (0.37, 95%CI 0.04-0.70), higher LV torsion, larger LA volume, worse PALS (∼2.4-fold) and greater LA stiffness (0.028, 95%CI 0.01-0.05). Increasing years of menopause was associated with further reduction in GLS, markedly worse LA mechanics despite greater LV sphericity and higher torsion. Lower estradiol levels correlated with more impaired LV diastolic function, impaired LV GLS, greater LA stiffness, and increased LV sphericity and LV torsion (all p < 0.05). Approximately 5.5% (37/669) of post-menopausal women incident HF over 2.9 years of follow-up. Greater LV sphericity [adjusted hazard ratio (aHR) 1.04, 95%CI 1.00-1.07], impaired GLS (aHR 0.87, 95%CI 0.78-0.97), reduced peak left atrial longitudinal strain (PALS, aHR 0.94, 95%CI 0.90-0.99) and higher LA stiffness (aHR 10.5, 95%CI 1.69-64.6) were independently associated with the primary outcome of HF hospitalizations in post-menopause. Both PALS < 23% (aHR:1.32, 95%CI 1.01-3.49) and GLS < 16% (aHR:5.80, 95%CI 1.79-18.8) remained prognostic for the incidence of HF in post-menopausal women in dichotomous analyses, even after adjusting for confounders. Results were consistent with composite outcomes of HF hospitalizations and 1-year all-cause mortality as well. Conclusion: Menopause was associated with greater LV/LA remodeling and reduced LV longitudinal and LA function in women. The cardiac functional deficit with menopause and lower estradiol levels, along with their independent prognostic value post-menopause, may elucidate sex differences in heart failure further.

AGE-BSA down-regulates endothelial connexin43 gap junctions.

BACKGROUND: Advanced glycation end products generated in the circulation of diabetic patients were reported to affect the function of vascular wall. We examined the effects of advanced glycation end products-bovine serum albumin (AGE-BSA) on endothelial connexin43 (Cx43) expression and gap-junction communication. RESULTS: In human aortic endothelial cells (HAEC) treated with a series concentrations of AGE-BSA (0-500 µg/ml) for 24 and 48 hours, Cx43 transcript and Cx43 protein were reduced in a dose dependent manner. In addition, gap-junction communication was reduced. To clarify the mechanisms underlying the down-regulation, MAPKs pathways in HAEC were examined. Both a MEK1 inhibitor (PD98059) and a p38 MAPK inhibitor (SB203580) significantly reversed the reductions of Cx43 mRNA and protein induced by AGE-BSA. Consistently, phosphorylation of ERK and p38 MAPK was enhanced in response to exposure to AGE-BSA. However, all reversions of down-regulated Cx43 by inhibitors did not restore the functional gap-junction communication. CONCLUSIONS: AGE-BSA down-regulated Cx43 expression in HAEC, mainly through reduced Cx43 transcription, and the process involved activation of ERK and p38 MAPK.

The incremental value of regional dyssynchrony in determining functional mitral regurgitation beyond left ventricular geometry after narrow QRS anterior myocardial infarction: a real time three-dimensional echocardiography study.

BACKGROUND: Determinants of functional mitral regurgitation (FMR) severity after acute anterior myocardial infarction (MI) remained unclear. Our aim was to: (1) test whether LV dyssynchrony upon real time three-dimensional echocardiography (RT-3DE) is independently associated with FMR severity; and (2) to investigate the role of regional systolic dyssynchrony index (SDI) in identifying FMR severity. METHODS: RT-3DE was successfully performed on 64 consecutive patients following acute anterior MI with a narrow QRS complex (<130 ms) and another 30 healthy volunteers. MR severity was assessed using vena contracta method. SDI was derived from the dispersion of the time to minimum regional volume for all 16 LV segments. Multiple linear regression analysis was used to identify the independent relationship between FMR and SDI with and without multivariate adjustment. RESULTS: The mean LV ejection fraction was 49.6%± 11.9% in the MI group. All regional (except apical) and global SDIs were associated with regional LV remodeling and were significantly correlated with FMR even after multivariate adjustment, with midwall SDI being most strongly associated with MR severity (R(2) = 0.55, P < 0.001). Regional midwall SDI superimposed on LV global geometry and mitral leaflet deformation substantially expanded the area under curve in identifying FMR (AUC increased from 0.69 to 0.93, c-statistics: P = 0.041). CONCLUSIONS: While both global and regional dyssynchrony following anterior MI were independently related to FMR severity, regional midwall dyssynchrony further added incremental value in predicting FMR severity beyond traditional parameters. This finding provides a new insight into the understanding of FMR after anterior MI and may further potentiate specific therapeutic approaches.

Diverse Adiposity and Atrio-Ventricular Dysfunction across Obesity Phenotypes: Implication of Epicardial Fat Analysis.

Obesity has been conceptualized as a highly heterogeneous condition. We aim to investigate chamber-specific effects of obesity on the heart and relevant outcomes. A total of 2944 symptom-free individuals (age: 47.5 ± 10.0 years), free of known cardiovascular diseases were classified into four categories based on body mass index (BMI) (as normal-weight (NW) vs. overweight/obese (O)) and metabolic status (metabolically-healthy (MH) vs. unhealthy (MU)). Epicardial adipose thickness (EAT) using echocardiography method. Speckle-tracking based atrio-ventricular (LA/LV) deformations including global longitudinal strain (GLS) and peak atrial longitudinal strain (PALS) were also analyzed. MUNW had higher cardiometabolic risks and more impaired diastolic and GLS/PALS than MHNW phenotype. Both MHO and MUO phenotypes exhibited worst atrial functions. Greater EAT was independently associated with worse GLS and PALS after correcting for various anthropometrics, LV mass and LA volume, respectively, with unfavorable LA effects from EAT being more pronounced in the NW phenotypes (both p interactions < 0.05). During a median follow-up period of 5.3 years, BMI/EAT improved the reclassification for atrial fibrillation (AF) incidence (p for net reclassification improvement < 0.05) mainly in the NW phenotypes (p interaction < 0.001). Categorization of clinical obesity phenotypes based on excessive visceral adiposity likely provides increment prognostic impacts on atrial dysfunction, particularly in non-obese phenotypes.

Association of free fatty acid binding protein with central aortic stiffness, myocardial dysfunction and preserved ejection fraction heart failure.

There is an established link between cardiometabolic abnormality, central arterial stiffness, and preserved ejection fraction heart failure (HFpEF). Adipocyte free fatty acid binding protein (a-FABP) has been shown to signal endothelial dysfunction through fatty acid toxicity, though its role in mediating ventricular-arterial dysfunction remains unclear. We prospectively examined the associations of a-FABP with central arterial pressure using non-invasive applanation tonometry (SphygmoCor) and cardiac structure/function (i.e., tissue Doppler imaging [TDI] and global longitudinal myocardial strain [GLS]) in patients with cardiometabolic (CM) risk (n = 150) and HFpEF (n = 50), with healthy volunteers (n = 49) serving as a control. We observed a graded increase of a-FABP across the healthy controls, CM individuals, and HFpEF groups (all paired p < 0.05). Higher a-FABP was independently associated with higher central systolic and diastolic blood pressures (CSP/CPP), increased arterial augmentation index (Aix), lower early myocardial relaxation velocity (TDI-e'), higher left ventricle (LV) filling (E/TDI-e') and worsened GLS (all p < 0.05). During a median of 3.85 years (interquartile range: 3.68-4.62 years) follow-up, higher a-FABP (cutoff: 24 ng/mL, adjusted hazard ratio: 1.01, 95% confidence interval: 1.001-1.02, p = 0.04) but not brain natriuretic peptide, and higher central hemodynamic indices were related to the incidence of heart failure (HF) in fully adjusted Cox models. Furthermore, a-FABP improved the HF risk classification over central hemodynamic information. We found a mechanistic pathophysiological link between a-FABP, central arterial stiffness, and myocardial dysfunction. In a population with a high metabolic risk, higher a-FABP accompanied by worsened ventricular-arterial coupling may confer more unfavorable outcomes in HFpEF.

Association of Region-Specific Cardiac Adiposity With Dysglycemia and New-Onset Diabetes.

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 ∆ ꭕ2: <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.

Visceral adiposity index outperforms conventional anthropometric assessments as predictor of diabetes mellitus in elderly Chinese: a population-based study.

BACKGROUND: This study assessed the performance of visceral adiposity index and body shape index in predicting diabetes mellitus (DM) risk and compared their predictive ability to that of body mass index and waist circumference. METHODS: Among 8249 consecutive subjects who attended the Nationwide Health Check Up System for Senior Citizens (≥ 65 years) between 2008 and 2018, we examined the associations of several adiposity indices with DM risk and explored gender differences. RESULTS: Among all adiposity indicators, Chinese visceral adiposity index (CVAI) demonstrated the highest discriminatory ability for diabetes mellitus with area under receiver operating characteristic curves (AUC) of 0.65, 0.68, and 0.66 for men, women, and all participants, respectively, and optimal cut-offs set as 126.09 in men and 117.77 in women. Compared with body shape index (ABSI), both CVAI and VAI were strongly associated with baseline DM (adjusted OR: 4.85, 95% CI: 4.05-5.82 and 4.22, 95% CI: 3.53-5.05 for 4th vs 1st quartile groups by CVAI and VAI, P < 0.001), which was more pronounced in older adult women (Pinteraction < 0.05). Over a median of 5.25 years (IQR: 3.07-6.44 years) follow-up, Cox regression models showed higher predictive ability of CVAI and VAI compared to ABSI. Further, both CVAI and VAI independently predicted new-onset DM (adjusted HR: 1.29, 95% CI: 1.22-1.37 and 1.16, 95% CI: 1.11-1.21 by CVAI and VAI) and composite endpoint of new DM and death among those without baseline DM. CONCLUSIONS: Our population-based data demonstrated that Chinese visceral adiposity index may serve as a superior clinical indicator of diabetes when compared with conventional anthropometric indices among older adult Chinese, especially in women.

Variant Aldehyde Dehydrogenase 2 (ALDH2*2) as a Risk Factor for Mechanical LA Substrate Formation and Atrial Fibrillation with Modest Alcohol Consumption in Ethnic Asians.

Aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism is a common genetic variant in Asians that is responsible for defective toxic aldehyde and lipid peroxidation metabolism after alcohol consumption. The extent to which low alcohol consumption may cause atrial substrates to trigger atrial fibrillation (AF) development in users with ALDH2 variants remains to be determined. We prospectively enrolled 249 ethnic Asians, including 56 non-drinkers and 193 habitual drinkers (135 (70%) as ALDH2 wild-type: GG, rs671; 58 (30%) as ALDH2 variants: G/A or A/A, rs671). Novel left atrial (LA) mechanical substrates with dynamic characteristics were assessed using a speckle-tracking algorithm and correlated to daily alcohol consumption and ALDH2 genotypes. Despite modest and comparable alcohol consumption by the habitual alcohol users (14.3 [8.3~28.6] and 12.3 [6.3~30.7] g/day for those without and with ALDH2 polymorphism, p = 0.31), there was a substantial and graded increase in the 4-HNE adduct and prolonged PR, and a reduction in novel LA mechanical parameters (including peak atrial longitudinal strain (PALS) and phasic strain rates (reservoir, conduit, and booster pump functions), p < 0.05), rather than an LA emptying fraction (LAEF) or LA volume index across non-drinkers, and in habitual drinkers without and with ALDH2 polymorphism (all p < 0.05). The presence of ALDH2 polymorphism worsened the association between increasing daily alcohol dose and LAEF, PALS, and phasic reservoir and booster functions (all Pinteraction: <0.05). Binge drinking superimposed on regular alcohol use exclusively further worsened LA booster pump function compared to regular drinking without binge use (1.66 ± 0.57 vs. 1.97 ± 0.56 1/s, p = 0.001). Impaired LA booster function further independently helped to predict AF after consideration of the CHARGE-AF score (adjusted 1.68 (95% CI: 1.06-2.67), p = 0.028, per 1 z-score increment). Habitual modest alcohol consumption led to mechanical LA substrate formation in an ethnic Asian population, which was more pronounced in subjects harboring ALDH2 variants. Impaired LA booster functions may serve as a useful predictor of AF in such populations.