Association of anthropometric measures with all-cause and cause-specific mortality in US adults: revisiting the obesity paradox.

OBJECTIVE: Previous studies have shown that the obesity paradox exists in a variety of clinical settings, whereby obese individuals have lower mortality than their normal-weight counterparts. It remains unclear whether the association between obesity and mortality risk varies by anthropometric measures. The purpose of this study is to examine the association between various anthropometric measures and all-cause and cause-specific mortality in US adults. METHODS: This cohort study included data from the National Health and Nutrition Examination Survey between 2009 and 2018, with a sample size of 28,353 individuals weighted to represent 231 million US adults. Anthropometric measurements were obtained by trained technicians using standardized methods. Mortality data were collected from the date of enrollment through December 31, 2019. Weighted Cox proportional hazards models, restricted cubic spline curves, and cumulative incidence analyses were performed. RESULTS: A total of 2091 all-cause deaths, 606 cardiovascular deaths, 519 cancer deaths, and 966 other-cause deaths occurred during a median follow-up of 5.9 years. The association between body mass index (BMI) and mortality risk was inversely J-shaped, whereas the association between waist-to-height ratio (WHtR) and mortality risk was positively J-shaped. There was a progressive increase in the association between the WHtR category and mortality risk. Compared with the reference category of WHtR < 0.5, the estimated hazard ratio (HR) for all-cause mortality was 1.004 (95% confidence interval [CI] 1.001-1.006) for WHtR 0.50-0.59, 1.123 (95% CI 1.120-1.127) for WHtR 0.60-0.69, 1.591 (95% CI 1.584-1.598) for WHtR 0.70-0.79, and 2.214 (95% CI 2.200-2.228) for WHtR ≥ 0.8, respectively. Other anthropometric indices reflecting central obesity also showed that greater adiposity was associated with higher mortality. CONCLUSIONS: Anthropometric measures reflecting central obesity were independently and positively associated with mortality risk, eliminating the possibility of an obesity paradox.

Impact of obesity on intensive care unit outcomes in older patients with critical illness: A cohort study.

BACKGROUND: Although the paradoxical association between obesity and improved survival has been reported in a variety of clinical settings, its applicability to intensive care unit (ICU) outcomes in older critically ill patients remains unclear. We sought to examine the association between obesity and 30-day mortality and other adverse outcomes in this population. METHODS: We analyzed data of older patients (≥ 60 years) in the eICU Collaborative Research Database. Body mass index (BMI) was stratified according to the World Health Organization obesity classification. Logistic regression model was used to estimate adjusted odds ratios (ORs), and cubic spline curve was used to explore the nonlinear association between BMI and 30-day ICU outcomes. Stratified analysis and sensitivity analysis were also performed. RESULTS: Compared with class I obesity, under- and normal-weight were associated with higher all-cause, cardiovascular and noncardiovascular mortality, and class III obesity was associated with greater all-cause and cardiovascular mortality (OR, 1.18 [95% CI, 1.06-1.32], 1.28 [1.08-1.51]). Obesity classes II and III were associated with higher composite all-cause mortality, mechanical ventilation, or vasoactive drug usage risks (OR, 1.12 [95% CI, 1.04-1.20], 1.33 [1.24-1.43]). Mechanical ventilation was strongly positively associated with BMI. A significant BMI-by-sex interaction was observed for cardiovascular mortality, such that the association between severe obesity and mortality was more pronounced among older men than older women. CONCLUSIONS: The obesity paradox does not appear to apply to short-term ICU outcomes in older patients with critical illness, mainly due to increased all-cause and cardiovascular mortality in severely obese patients, particularly in men.

Impact of obesity on all-cause and cause-specific mortality among critically ill men and women: a cohort study on the eICU database.

Background: The effect of obesity on intensive care unit outcomes among critically ill patients and whether there are sex differences have not been well investigated. We sought to determine the association between obesity and 30-day all-cause and cause-specific mortality among critically ill men and women. Methods: Adult participants who had body mass index (BMI) measurements were included from the eICU database. Participants were divided into six groups according to BMI (kg/m2) categories (underweight, <18.5; normal weight, 18.5-24.9; overweight, 25-29.9; class I obesity, 30-34.9; class II obesity, 35-39.9; class III obesity, ≥40). A multivariable adjusted logistic model was conducted with odds ratios (ORs) and 95% confidence intervals (CIs). A cubic spline curve based on the generalized additive model was used to represent the nonlinear association. Stratified analysis and sensitivity analysis were also performed. Results: A total of 160,940 individuals were included in the analysis. Compared with the class I obesity category, the underweight and normal weight categories had higher all-cause mortality, and the multivariable adjusted ORs were 1.62 (95% CI: 1.48-1.77) and 1.20 (95% CI: 1.13-1.27) for the general population, 1.76 (95% CI: 1.54-2.01) and 1.22 (95% CI: 1.13-1.32) for men, and 1.51 (95% CI: 1.33-1.71) and 1.16 (95% CI: 1.06-1.27) for women, respectively. Accordingly, multivariable adjusted ORs for the class III obesity category were 1.14 (95% CI: 1.05-1.24) for the general population, 1.18 (95% CI: 1.05-1.33) for men, and 1.10 (95% CI: 0.98-1.23) for women. With cubic spline curves, the association between BMI and all-cause mortality was U-shaped or reverse J-shaped. Similar findings were observed for cause-specific mortality, with the underweight category associated with a higher risk of mortality. Class III obesity increased the risk of cardiovascular death among men (OR 1.51; 95% CI: 1.23-1.84) and increased the risk of other-cause death among women (OR 1.33; 95% CI: 1.10-1.61). Conclusion: The obesity paradox appears to be suitable for all-cause and cause-specific mortality among critically ill men and women. However, the protective effect of obesity cannot be extended to severely obese individuals. The association between BMI and cardiovascular mortality was sex-specific and was more pronounced among men than among women. Graphical abstract.

U-Shaped Relationship of Sodium-to-chloride Ratio on admission and Mortality in Elderly Patients with Heart Failure: A Retrospective Cohort Study.

Serum sodium and chloride have clinical significance in the prognosis of heart failure. Little is known regarding the prognostic value of sodium-to-chloride (Na/Cl) ratio in patients with heart failure. This study sought to investigate the association between Na/Cl ratio on admission and mortality risk of elderly patients with acute heart failure in a retrospective cohort. We included 1819 patients (aged over 60) from the Zigong Heart Failure Study. Patients were grouped according to Na/Cl ratio and followed up for all-cause mortality at 3 months. Restricted cubic spline, cox proportional hazard regression and Kaplan-Meier curve were used to examine the correlation between serum Na/Cl ratio on admission and mortality risk. Restricted cubic spline analysis suggested a U-shaped association between Na/Cl ratio on admission and 3 months mortality risk (P nonlinearity <0.001), with the nadir of risk at 1.34. After adjustment for multivariate, patients with Na/Cl ratio <1.3 or ≥ 1.4 had hazard ratios for mortality of 3.58 (95% CI, 1.63-7.84) and 2.66 (95% CI, 1.23-5.72) compared with those with Na/Cl ratio of 1.3-1.4. The cumulative hazard of mortality estimates significantly differed across Na/Cl ratio groups (log-rank P<0.001). Subgroup analysis showed there were no interactions with absent or present of hyponatremia and hypochloremia (P for interaction all >0.05). Both low and high Na/Cl ratios were associated with an increased mortality risk in elderly patients with acute heart failure. Further studies need to verify these 2 biochemical phenotypes and develop corresponding treatment strategies.

Serum Chloride Is Inversely Associated With 3 Months Outcomes in Chinese Patients With Heart Failure, a Retrospective Cohort Study.

Background: Serum chloride was recently found to be associated with prognosis of heart failure in western countries. However, the evidence was scarce in Asia. We aimed to investigated the relationship between serum chloride and clinical outcomes in a Chinese cohort with hospitalized heart failure. Methods: We retrospectively analyzed the data from PhysioNet, involving 1996 patients who were admitted with heart failure between December 2016 and June 2019. Outcome was a composite endpoint of all-cause death or rehospitalization at 3 months. Results: The incidence of the composite endpoint was 26.8% (535/1,996); it was 32.2% (213/662), 25.0% (165/661), and 23.3% (157/673) by chloride tertiles (from the lowest to the highest), respectively. The serum chloride at admission was independently and inversely associated with the composite endpoint risk (hazard ratio: 0.967; 95% confidence interval: 0.939 to 0.996; p = 0.026) in contrast to sodium, which was no longer significant (p > 0.05) after multivariable adjustment. Pearson correlation between serum chloride and sodium was 0.747 (p < 0.001). However, an increased AUC was not observed by adding sodium to model composed of age, sex, NYHA class, diabetes, log BNP and chloride (0.620 vs. 0.612, p = 0.132). Subgroup analysis showed the presence or absence of hyponatremia did not affect the association between chloride and composite endpoint risk. Conclusions: Low serum chloride at admission was associated with poor outcomes in Chinese hospitalized patients with heart failure. These findings warrant future studies for tackling the potential pathophysiological mechanisms and correction methods of hypochloremia in heart failure.

Pretreatment of Adipose Derived Stem Cells with Curcumin Facilitates Myocardial Recovery via Antiapoptosis and Angiogenesis.

The poor survival rate of transplanted stem cells in ischemic myocardium has limited their therapeutic efficacy. Curcumin has potent antioxidant property. This study investigates whether prior curcumin treatment protects stem cells from oxidative stress injury and improves myocardial recovery following cells transplantation. Autologous Sprague-Dawley rat adipose derived mesenchymal stem cells (ADSCs) were pretreated with or without curcumin. The hydrogen peroxide/serum deprivation (H2O2/SD) medium was used to mimic the ischemic condition in vitro. Cytoprotective effects of curcumin on ADSCs were evaluated. Curcumin pretreatment significantly increased cell viability and VEGF secretion, and decreased cell injury and apoptosis via regulation of PTEN/Akt/p53 and HO-1 signal proteins expression. The therapeutic potential of ADSCs implantation was investigated in myocardial ischemia-reperfusion injury (IRI) model. Transplantation of curcumin pretreated ADSCs not only resulted in better heart function, higher cells retention, and smaller infarct size, but also decreased myocardial apoptosis, promoted neovascularization, and increased VEGF level in ischemic myocardium. Together, priming of ADSCs with curcumin improved tolerance to oxidative stress injury and resulted in enhancement of their therapeutic potential of ADSCs for myocardial repair. Curcumin pretreatment is a promising adjuvant strategy for stem cells transplantation in myocardial restoration.

Central venous catheter-related thrombosis in senile male patients: New risk factors and predictors.

Central venous catheterization (CVC)-related venous thrombosis is a common but serious clinical complication, thus prevention and treatment on this problem should be extensively investigated. In this research, we aimed to investigate the incidence rate of CVC-related venous thrombosis in senile patients and give a further discussion on the related risk factors and predictors. A total of 324 hospitalized senile male patients subjected to CVC were selected. Retrospective investigation and analysis were conducted on age, underlying diseases, clinical medications, catheterization position and side, catheter retention time, and incidence of CVC-related venous thrombosis complications. Basic laboratory test results during catheterization and thrombogenesis were also collected and analyzed. Among the 324 patients, 20 cases (6.17%) of CVC-related venous thrombosis were diagnoseds. The incidence rate of CVC-related venous thrombosis in subclavian vein catheterization was significantly lower than that in femoral vein catheterization (P<0.01) and that in internal jugular vein catheterization (P<0.05). No statistically significant difference was found between femoral vein catheterization and internal jugular vein catheterization (P<0.05). Previous venous thrombosis history (P<0.01), high lactate dehydrogenase level (P<0.01), low high-density lipoprotein (HDL) level (P<0.05), and low albumin level (P<0.05) were found as risk factors or predictors of CVC-related venous thrombosis in senile male patients. Subclavian vein catheterization was the most appropriate choice among senile patients to decrease the incidence of CVC-related venous thrombosis. Previous venous thrombosis history, high lactate dehydrogenase level, low HDL level, and low albumin level were important risk factors in predicting CVC-related venous thrombosis.

Association of serum androgen concentrations with cardiovascular risk factors in elderly male patients with chronic systolic heart failure in China.

OBJECTIVE: To survey the serum androgen concentrations and investigate the relationship between androgen levels and cardiovascular risk factors in elderly male patients with chronic systolic heart failure (HF) in China. METHODS: 106 consecutive male patients hospitalized for chronic systolic HF aged from 60 to 87 were enrolled. About 400 healthy age-matched men were compared as a control group. Total testosterone (TT), free testosterone (FT), dehydroepiandrosterone sulfate (DHEAS) and sex hormone binding globulin (SHBG) were measured. Differences of androgen levels between HF patients and healthy men were determined by t-test and associations of androgen with cardiovascular risk factors were evaluated by partial correlations analyses. RESULTS: Compared with healthy men, TT, FT and DHEAS levels in patients with HF decreased, whereas SHBG level increased significantly (both p < 0.01). TT was negatively correlated with TC, TG and DBP (p < 0.05), FT was negatively correlated with TC, LDL-C and DBP (p < 0.05). SHBG correlated with BMI and smoking history positively (p < 0.05). CONCLUSIONS: Level of bio-available testosterone decreased with advancing age, especially in men with HF. Men with low levels of bio-available testosterone had worse profiles of cardiovascular risk factors. Treatment of HF is still challenging and testosterone supplementation therapy may be an effective therapeutic option.

Polymorphisms of angiotensin-converting enzyme 2 gene confer a risk to lone atrial fibrillation in Chinese male patients.

BACKGROUND: Growing epidemiologic evidence has indicated that genetics can predispose individuals to the occurrence of lone atrial fibrillation (AF). The angiotensin-converting enzyme 2 (ACE2) gene has been established to be associated with hypertension and left ventricular hypertrophy. The objective of our study was to investigate the association of ACE2 gene polymorphisms with lone AF. METHODS: A total of 265 consecutive lone AF patients and 289 healthy controls were successfully investigated. The polymorphisms rs2106809 and rs2285666 were genotyped by polymerase chain reaction (PCR) and direct sequencing. A Logistic regression model was used to determine the odds ratio (OR) and 95% confidence intervals (CI) of variations of ACE2 for lone AF. RESULTS: The T allele of rs2106809 conferred an increased risk for lone AF (OR 1.24, 95% CI 1.01-1.52, P = 0.03) in males after adjustment for conventional risk factors. SNP at rs2285666 in males was not significantly different between AF patients and controls. No association was found between the two polymorphisms in the female population with lone AF. After (36.3 ± 4.5) months of follow-up, the end point data were obtained: death (cardiac and noncardiac), ischemic stroke, and heart failure. In the male subgroup, the associations between rs2106809 T male carriers and combined end points including ischemic stroke, heart failure, and death in our study were of significance (OR 3.6, 95% CI 1.0-13.1, P = 0.04). CONCLUSIONS: The results indicate that polymorphism at ACE2 gene is associated with male lone AF in a Chinese Han population. Lone AF males who carry the rs2106809 T allele are associated with adverse cardiac events.

Ameliorated stress related proteins are associated with improved cardiac function by sarcoplasmic reticulum calcium ATPase gene transfer in heart failure.

BACKGROUND: Previous studies showed that overexpression of sarco-endoplasmic reticulum calcium ATPase (SERCA2a) in a variety of heart failure (HF) models was associated with greatly enhanced cardiac performance. However, it still undefined the effect of SERCA2a overexpression on the systemic inflammatory response and neuro-hormonal factors. METHODS: A rapid right ventricular pacing model of experimental HF was used in beagles. Then the animals underwent recombinant adeno-associated virus 1 (rAAV1) mediated gene transfection by direct intra-myocardium injection. HF animals were randomized to receive the SERCA2a gene, enhanced green fluorescent protein (control) gene, or equivalent phosphate buffered saline. Thirty days after gene delivery, the cardiac function was evaluated by echocardiographic testing. The protein level of SERCA2a was measured by western blotting. The proteomic analysis of left ventricular (LV) sample was determined using two-dimensional (2-D) gel electrophoresis and MALDI-TOF-MS. The serum levels of the systemic inflammatory and neuro-hormonal factors were assayed using radioimmunoassay kits. RESULTS: The cardiac function improved after SERCA- 2a gene transfer due to the significantly increased SERCA2a protein level. Beagles treated with SERCA2a had significantly decreased serum levels of the inflammatory markers (interleukin-6 and tumor necrosis factor-α) and neuro-hormonal factors (brain natriuretic peptide, endothelin-1 and angiotensin II) compared with HF animals. The myocardial proteomic analysis showed that haptoglobin heavy chain, heat shock protein (alpha-crystallin-related, B6) were down-regulated, and galectin-1 was up-regulated in SERCA2a group compared with HF group, companied by up-regulated contractile proteins and NADH dehydrogenase. CONCLUSIONS: These findings demonstrate that regional intramyocardial injections of rAAV1-SERCA2a vectors may improve global LV function, correlating with reverse activation of the systemic inflammatory, excessive neuroendocrine factors and the stress-associated myocardial proteins, suggesting that the beneficial effects of SERCA2a gene transfer may involve the attenuation of stress-associated reaction.

Improvement in cardiac function after sarcoplasmic reticulum Ca2+-ATPase gene transfer in a beagle heart failure model.

BACKGROUND: Heart failure (HF) is a major cause of morbidity and mortality worldwide, but current treatment modalities cannot reverse the underlying pathological state of the heart. Gene-based therapies are emerging as promising therapeutic modalities in HF patients. Our previous studies have shown that recombinant adeno-associated viral (rAAV) gene transfer of Sarco-endoplasmic reticulum calcium ATPase (SERCA2a) can be effective in treating rats with chronic heart failure (CHF). The aim of this study was to examine the effects of SERCA2a gene transfer in a large HF animal model. METHODS: HF was induced in beagles by rapid right ventricular pacing (230 beats/min) for 30 days. A reduced rate ventricular pacing (180 beats/min) was continued for another 30 days. The beagles were assigned to four groups: (a) control group (n = 4); (b) HF group (n = 4); (c) enhanced green fluorescent protein group (n = 4); and (d) SERCA2a group (n = 4). rAAV1-EGFP (1 x 10(12) microg) and rAAV1-SERCA2a (1 x 10(12) microg) were delivered intramyocardially. SERCA2a expression was assessed by Western blotting and immunohistochemistry. RESULTS: Following 30 days of SERCA2a gene transfer in HF beagles its protein expression was significantly higher than in the HF group than in the control group (P < 0.05). Heart function improved along with the increase in SERCA2a expression. Left ventricular systolic function significantly improved, including the ejection fraction, left ventricular systolic pressure, maximal rate of rise of left ventricular pressure (+dp/dt(max)), and the maximal rate of decline of left ventricular pressure (-dp/dt(max)) (P < 0.05). Left ventricular end-diastole pressure significantly decreased (P < 0.05). The expression of SERCA2a in the myocardial tissue was higher in the SERCA2a group than in the HF group (P < 0.05). CONCLUSIONS: Intramyocardial injection of rAAV1-SERCA2a can improve the cardiac function in beagles induced with HF. We expect further studies on SERCA2a's long-term safety, efficacy, dosage and the optimization before using it in humans with HF.

[Overexpression of sarcoplasmic reticulum calcium ATPase induced hemodynamic and proteomic changes in a dog model of heart failure].

OBJECTIVE: Overexpression of SERCA2a could improve cardiac function in human and experimental heart failure (HF) models. We observed the proteomics changes post SERCA2a overexpression in a pacing induced HF model in dogs. METHODS: Beagles were divided into four groups: control group, HF group (230 beats/min for 4 weeks), HF + EGFP group (myocardial injection of 1 x 10(12) v.g recombinant adeno-associated virus carrying enhanced green fluorescent protein gene, rAAV2/1-EGFP) and HF + SERCA2a group (myocardial injection of 1 x 10(12) v.g recombinant adeno-associated virus carrying SERCA2a gene, rAAV2/1-SERCA2a). Thirty days after gene transduction, left ventricular systolic and diastolic functions were measured by echocardiography and invasive hemodynamics in all animals. By use of 2-dimensional gel electrophoresis (2-DE), -500 distinct protein spots were detected in myocardium of all animals. Protein spots observed to be altered between failing and SERCA2a overexpressed hearts were subjected to tryptic peptide mass fingerprinting for identification by MALDI-TOF mass spectrometry in combination with LC/MS/MS analysis. RESULTS: At 30 day after gene transfer, HF signs were significantly reduced, cardiac function [LVSP: (214.72 +/- 31.74) mm Hg (1 mm Hg = 0.133 kPa) vs. (139.32 +/- 36.79) mm Hg, +dp/dt(max): (6779.43 +/- 217.58) mm Hg/s vs. (2746.85 +/- 931.23) mm Hg/s and -dp/dt(max): (-4341.42 +/- 322.02) mm Hg/s vs. (-2531.14 +/- 616.15) mm Hg/s, LVEDP: (21.86 +/- 6.95) mm Hg vs. (59.78 +/- 6.92) mm Hg] significantly improved in HF + SERCA2a dogs than those in HF + EGFP group(all P < 0.05) and parameters were comparable between HF + SERCA2a and control groups. We identified alterations in the expression level of more than 10 proteins in myocardium. These protein changes were observed mainly in two subcellular compartments: the cardiac contractile apparatus and metabolism/energetics. CONCLUSION: These results showed that overexpression of SERCA2a could improve cardiac function accompanied with numerous alterations in protein expressions involved in calcium handling, myofibrils, and energy production in this dog model of chronic heart failure.