Dose-Response Relationship of Physical Activity to Premature and Total All-Cause and Cardiovascular Disease Mortality in Walkers

Purpose

To assess the dose-response relationships between cause-specific mortality and exercise energy expenditure in a prospective epidemiological cohort of walkers.

Methods

The sample consisted of the 8,436 male and 33,586 female participants of the National Walkers'' Health Study. Walking energy expenditure was calculated in metabolic equivalents (METs, 1 MET = 3.5 ml O₂/kg/min), which were used to divide the cohort into four exercise categories: category 1 (≤1.07 MET-hours/d), category 2 (1.07 to 1.8 MET-hours/d), category 3 (1.8 to 3.6 MET-hours/d), and category 4 (≥3.6 MET-hours/d). Competing risk regression analyses were use to calculate the risk of mortality for categories 2, 3 and 4 relative to category 1.

Results

22.9% of the subjects were in category 1, 16.1% in category 2, 33.3% in category 3, and 27.7% in category 4. There were 2,448 deaths during the 9.6 average years of follow-up. Total mortality was 11.2% lower in category 2 (P = 0.04), 32.4% lower in category 3 (P<10⁻¹²) and 32.9% lower in category 4 (P = 10⁻¹¹) than in category 1. For underlying causes of death, the respective risk reductions for categories 2, 3 and 4 were 23.6% (P = 0.008), 35.2% (P<10⁻⁵), and 34.9% (P = 0.0001) for cardiovascular disease mortality; 27.8% (P = 0.18), 20.6% (P = 0.07), and 31.4% (P = 0.009) for ischemic heart disease mortality; and 39.4% (P = 0.18), 63.8% (P = 0.005), and 90.6% (P = 0.002) for diabetes mortality when compared to category 1. For all related mortality (i.e., underlying and contributing causes of death combined), the respective risk reductions for categories 2, 3 and 4 were 18.7% (P = 0.22), 42.5% (P = 0.001), and 57.5% (P = 0.0001) for heart failure; 9.4% (P = 0.56), 44.3% (P = 0.0004), and 33.5% (P = 0.02) for hypertensive diseases; 11.5% (P = 0.38), 41.0% (P<10⁻⁴), and 35.5% (P = 0.001) for dysrhythmias: and 23.2% (P = 0.13), 45.8% (P = 0.0002), and 41.1% (P = 0.005) for cerebrovascular diseases when compared to category 1.

Conclusions

There are substantial health benefits to exceeding the current exercise guidelines.     

High Mortality from Blood Stream Infection in Addis Ababa,Ethiopia, Is Due to Antimicrobial Resistance

Background

Managing blood stream infection in Africa is hampered by lack of bacteriological support needed for antimicrobial stewardship, and background data needed for empirical treatment. A combined pro- and retrospective approach was used to overcome thresholds in clinical research in Africa.

Methods

Outcome and characteristics including age, HIV infection, pancytopenia and bacteriological results were studied in 292 adult patients with two or more SIRS criteria using univariate and confirming multivariate logistic regression models. Expected randomly distributed resistance covariation was compared with observed co-resistance among gram-negative enteric bacteria in 92 paediatric blood culture isolates that had been harvested in the same hospital during the same period of time.

Results

Mortality was fivefold increased among patients with positive blood culture results [50.0% vs. 9.8%; OR 11.24 (4.38–25.88), p < 0.0001], and for this group of patients mortality was significantly associated with antimicrobial resistance [OR 23.28 (3.3–164.4), p = 0.002]. All 11 patients with Enterobacteriaceae resistant to 3^rd. generation cephalosporins died. Eighty-nine patients had pancytopenia grade 3–4. Among patients with negative blood culture results, mortality was significantly associated with pancytopenia [OR 3.12 (1.32–7.39), p = 0.01]. HIV positivity was not associated with increased mortality. Antimicrobial resistance that concerned gram-negative enteric bacteria, regardless of species, was characterized by co-resistance between third generation cephalosporins, gentamicin, chloramphenicol, and co-trimoxazole.

Conclusion

Mortality was strongly associated with growth of bacteria resistant to empirical treatment, and these patients were dead or dying when bacteriological reports arrived. Because of co-resistance, alternative efficient antibiotics would not have been available in Ethiopia for 8/11 Enterobacteriaceae-infected patients with isolates resistant to third generation cephalosporins. Strong and significant resistance covariation between 3^rd. generation cephalosporins, chloramphenicol, gentamicin, and co-trimoxazole was identified. Pronounced pancytopenia was common and associated with increased mortality. HIV positive patients had no excess mortality.     

Mortality Due to Malignant and Non-Malignant Diseases in Korean Professional Emergency Responders

ObjectiveThis study was conducted to estimate the cause-specific mortality in male emergency responders (ER), compare with that of Korean men. Mortality was also compared between more experienced firefighters (i.e., firefighters employed ≥20 years and firefighters employed ≥10 to <20 years) and less experienced firefighters and non-firefighters (i.e., firefighters employed <10 years and non-firefighters) to investigate associations between mortality and exposure to occupational hazards.MethodsThe cohort was comprised of 33,442 males who were employed as ERs between 1980 and 2007 and not deceased as of 1991. Work history was merged with the death registry from the National Statistical Office of Korea to follow-up on mortality between 1992 and 2007. Standardized mortality ratios (SMR) for ERs were calculated in reference to the Korean male population. Adjusted relative risks (ARRs) of mortalities for firefighters employed ≥20 years and ≥10 years to <20 years were calculated in reference to non-firefighters and firefighters employed < 10 years.ResultsOverall (SMR=0.43, 95%CI=0.39–0.47) and some kinds of cause-specific mortalities were significantly lower among ERs compared with the Korean male population. No significant increase in mortality was observed across the major ICD-10 classifications among ERs. Mortality due to exposure to smoke, fire, and flames (SMR=3.11, 95% CI=1.87–4.85), however, was significantly increased among ERs. All-cause mortality (ARR=1.46, 95% CI=1.13–1.89), overall cancer mortality (ARR=1.54, 95% CI=1.02–2.31) and mortality of external injury, poisoning and external causes (ARR=3.13, 95% CI=1.80–5.46) were significantly increased among firefighters employed ≥20 years compared to those of non-firefighters and firefighters employed < 10 years.ConclusionsAn increase in mortality due to all cancer and external injury, poisoning, and external causes in firefighters employed ≥20 years compared with non-firefighters and firefighters employed <10 years suggests occupational exposure.     

Obesity Indexes and Total Mortality among Elderly Subjects at High Cardiovascular Risk: The PREDIMED Study

Background

Different indexes of regional adiposity have been proposed for identifying persons at higher risk of death. Studies specifically assessing these indexes in large cohorts are scarce. It would also be interesting to know whether a dietary intervention may counterbalance the adverse effects of adiposity on mortality.

Methods

We assessed the association of four different anthropometric indexes (waist-to-height ratio (WHtR), waist circumference (WC), body mass index (BMI) and height) with all-cause mortality in 7447 participants at high cardiovascular risk from the PREDIMED trial. Forty three percent of them were men (55 to 80 years) and 57% were women (60 to 80 years). All of them were initially free of cardiovascular disease. The recruitment took place in 11 recruiting centers between 2003 and 2009.

Results

After adjusting for age, sex, smoking, diabetes, hypertension, intervention group, family history of coronary heart disease, and leisure-time physical activity, WC and WHtR were found to be directly associated with a higher mortality after 4.8 years median follow-up. The multivariable-adjusted HRs for mortality of WHtR (cut-off points: 0.60, 0.65, 0.70) were 1.02 (0.78–1.34), 1.30 (0.97–1.75) and 1.55 (1.06–2.26). When we used WC (cut-off points: 100, 105 and 110 cm), the multivariable adjusted Hazard Ratios (HRs) for mortality were 1.18 (0.88–1.59), 1.02 (0.74–1.41) and 1.57 (1.19–2.08). In all analyses, BMI exhibited weaker associations with mortality than WC or WHtR. The direct association between WHtR and overall mortality was consistent within each of the three intervention arms of the trial.

Conclusions

Our study adds further support to a stronger association of abdominal obesity than BMI with total mortality among elderly subjects at high risk of cardiovascular disease. We did not find evidence to support that the PREDIMED intervention was able to counterbalance the harmful effects of increased adiposity on total mortality.

Trial Registration

Controlled-Trials.com ISRCTN35739639     

The Association between Neuroticism and Heart Rate Variability Is Not Fully Explained by Cardiovascular Disease and Depression

Neuroticism is associated with cardiovascular disease, autonomic reactivity, and depression. Here we address the extent to which neuroticism accounts for the excess heart disease risk associated with depression and test whether cardiac autonomic tone plays a role as mediator. Subjects were derived from a nationally representative sample (n = 1,255: mean age 54.5, SD = 11.5). Higher neuroticism was associated with reduced heart rate variability equally under rest and stress. The baseline structural equation model revealed significant paths from neuroticism to heart rate variability, cardiovascular disease and depression, and between depression and cardiovascular disease, controlling for age, sex, height, weight, and BMI. Dropping both the neuroticism to heart rate variability, and neuroticism to heart disease paths significantly reduced the model fit (p < .001 in each case). We conclude that neuroticism has independent associations with both autonomic reactivity and cardiovascular disease, over and above its associations with depression and other related variables.     

Stress-Induced Grey Matter Loss Determined by MRI Is Primarily Due to Loss of Dendrites and Their Synapses

Stress, unaccompanied by signs of post-traumatic stress disorder, is known to decrease grey matter volume (GMV) in the anterior cingulate cortex (ACC) and hippocampus but not the amygdala in humans. We sought to determine if this was the case in stressed mice using high-resolution magnetic resonance imaging (MRI) and to identify the cellular constituents of the grey matter that quantitatively give rise to such changes. Stressed mice showed grey matter losses of 10 and 15 % in the ACC and hippocampus, respectively but not in the amygdala or the retrosplenial granular area (RSG). Concurrently, no changes in the number or volumes of the somas of neurons, astrocytes or oligodendrocytes were detected. A loss of synaptic spine density of up to 60 % occurred on different-order dendrites in the ACC and hippocampus (CA1) but not in the amygdala or RSG. The loss of spines was accompanied by decreases in cumulative dendritic length of neurons of over 40 % in the ACC and hippocampus (CA1) giving rise to decreases in volume of dendrites of 2.6 mm³ for the former and 0.6 mm³ for the latter, with no change in the amygdala or RSG. These values are similar to the MRI-determined loss of GMV following stress of 3.0 and 0.8 mm³ in ACC and hippocampus, respectively, with no changes in the amygdala or RSG. This quantitative study is the first to relate GMV changes in the cortex measured with MRI to volume changes in cellular constituents of the grey matter.     

Parathyroidectomy Is Associated With Reversed Nondipping Heart Rate That Impacts Mortality in Chronic Kidney Disease Patients

ObjectiveNondipping heart rate (HR), defined as a night/day HR ratio >0.90, has been associated with increased mortality in epidemiologic studies. However, its prognostic value in stage 5 chronic kidney disease (CKD5) patients and the effects of parathyroidectomy (PTX) on nondipping HR remain unknown.MethodsThis case-control study of 162 healthy controls and 502 CKD5 patients was performed between 2011 and 2018, in which CKD5 patients were further divided into non-PTX (n = 186) and severe secondary hyperparathyroidism (SHPT) with PTX (n = 316) subgroups. Each participant underwent 24-hour Holter monitoring for HR ratio. Mortality was followed up in CKD5 patients (median time: 46.0 months).ResultsThe HR ratio in CKD5 patients was higher than in controls (0.92 ± 0.08 vs 0.81 ± 0.08, P <.001), associated with a 44% increase in mortality risk per 0.1 increment (hazard ratio, 1.44; 95% CI: 1.02-2.03; P =.04), and was positively related to serum intact parathyroid hormone levels (P <.001). PTX reversed nondipping HR in SHPT patients (n = 50, median time: 6.3 months, P <.001). Survival probabilities for PTX (n = 294) were better than non-PTX (n = 47) (hazard ratio, 0.31; 95% CI: 0.14-0.67; P <.01) in SHPT patients (serum intact parathyroid hormone >500.0 pg/mL).ConclusionCKD5 patients displayed a nondipping HR pattern, which is a prognostic marker of all-cause mortality. PTX for SHPT patients was associated with a reversal in nondipping HR ratio, which may mediate a better outcome.     

NT-proBNP Best Predictor of Cardiovascular Events and Cardiovascular Mortality in Secondary Prevention in Very Old Age: The Leiden 85-Plus Study

Background

In the aging population cardiovascular disease (CVD) is highly prevalent. Identification of very old persons at high risk of recurrent CVD is difficult, since traditional risk markers loose predictive value with age.

Methods

In a population-based sample of 282 85-year old participants with established CVD from the Leiden 85-plus Study, we studied predictive values of traditional cardiovascular risk markers, a history of major CVD (myocardial infarction, stroke or arterial surgery), and new cardiovascular biomarkers (estimated glomerular filtration rate (MDRD), C-reactive protein (CRP), homocysteine and N-terminal pro B-type natriuretic peptide (NT-proBNP)) regarding 5-year risk of recurrent cardiovascular events and mortality (composite endpoint).

Results

During complete 5-year follow-up 157 (56%) participants died. 109 (39%) had a cardiovascular event or died from cardiovascular causes. Individually related to the composite endpoint were: a history of major CVD (HR 1.5 (95%CI 1.03-2.3)), CRP (HR 1.3 (95%CI 1.03-1.5)), homocysteine (HR 1.4 (95%CI 1.2-2.6)) and NT-proBNP (HR 1.7 (95%CI 1.4-2.1)). A prediction model including all traditional risk markers yielded a C-statistic of 0.59 (95%CI 0.52-0.66). Of all five new markers only addition of NT-proBNP improved the C-statistic (0.67 (95%CI 0.61-0.74, p=0.023)). The categoryless net reclassification improvement for NT-proBNP was 39% (p=0.001), for a history of major CVD 27.2% (p=0.03) and for homocysteine 24.7% (p=0.04).

Conclusions

Among very old subjects with established CVD, NT-proBNP was the strongest risk marker for cardiovascular events and cardiovascular mortality. When estimating risk in secondary prevention in very old age, use of NT-proBNP should be considered.     

The MitCHAP-60 Disease Is Due to Entropic Destabilization of the Human Mitochondrial Hsp60 Oligomer

The 60-kDa heat shock protein (mHsp60) is a vital cellular complex that mediates the folding of many of the mitochondrial proteins. Its function is executed in cooperation with the co-chaperonin, mHsp10, and requires ATP. Recently, the discovery of a new mHsp60-associated neurodegenerative disorder, MitCHAP-60 disease, has been reported. The disease is caused by a point mutation at position 3 (D3G) of the mature mitochondrial Hsp60 protein, which renders it unable to complement the deletion of the homologous bacterial protein in Escherichia coli (Magen, D., Georgopoulos, C., Bross, P., Ang, D., Segev, Y., Goldsher, D., Nemirovski, A., Shahar, E., Ravid, S., Luder, A., Heno, B., Gershoni-Baruch, R., Skorecki, K., and Mandel, H. (2008) Am. J. Hum. Genet. 83, 30–42). The molecular basis of the MitCHAP-60 disease is still unknown. In this study, we present an in vitro structural and functional analysis of the purified wild-type human mHsp60 and the MitCHAP-60 mutant. We show that the D3G mutation leads to destabilization of the mHsp60 oligomer and causes its disassembly at low protein concentrations. We also show that the mutant protein has impaired protein folding and ATPase activities. An additional mutant that lacks the first three amino acids (N-del), including Asp-3, is similarly impaired in refolding activity. Surprisingly, however, this mutant exhibits profound stabilization of its oligomeric structure. These results suggest that the D3G mutation leads to entropic destabilization of the mHsp60 oligomer, which severely impairs its chaperone function, thereby causing the disease.Type I chaperonins are essential molecular chaperones of the Hsp60 family found in eubacteria, mitochondria, and chloroplasts (1). They are key players in mediating the correct folding of newly translated, translocated, and stress-denatured proteins. The folding function of chaperonins is executed by the coordinated action of two oligomeric proteins, Hsp60 (also named cpn60 and in bacteria GroEL) and its co-chaperonin Hsp10 (also named cpn10 and in bacteria GroES). The GroEL molecule is composed of 14 subunits that form a barrel-like structure that consists of two back-to-back stacked heptameric rings with a large cavity at each end termed the “Anfinsen cage.” GroES is a heptameric ring formed by ∼10-kDa subunits. The co-chaperonin binds to the chaperonin in the presence of ATP and Mg²⁺ via a short, unstructured, but highly conserved region known as the mobile loop (2, 3). Due to the stability of the GroEL/ES oligomers and the ease with which they can be purified from bacteria, they have become the primary targets for study in the field of chaperonins. As a result, almost all of our knowledge concerning the structure and mechanism of chaperonins, both Hsp60 and Hsp10, is based largely on data from experiments on these E. coli proteins. The chaperonin reaction cycle starts when a non-folded protein substrate binds to the surface of the cavity of one of the GroEL rings. ATP-dependent GroES binding to that (cis) ring causes a dramatic conformational change that leads to a doubling of the cavity size and a switch in the cavity surface from being hydrophobic to hydrophilic. These conformational changes trigger the release of the encapsulated substrate protein into the cavity, where it can fold in a protected environment (4–9). Subsequent binding of ATP and GroES to the opposite (trans) ring promotes the release of GroES, ADP, and protein substrate from the cis ring into bulk solution.The homologous mitochondrial chaperonin system was shown to be responsible for refolding proteins imported into the mitochondria (10, 11). The mitochondrial Hsp60 (mHsp60)³ is similar to GroEL in that it is made up of heptameric rings (12–14) that can refold denatured substrates in vitro with the assistance of a co-chaperonin and ATP (15). However, the mHsp60 oligomer is less stable than the bacterial homolog, and it exhibits unique nucleotide binding properties and specificity for co-chaperonin (13, 14, 16).In addition to their essential function in mediating protein folding, the mammalian mitochondrial chaperonins were also suggested to be involved in extramitochondrial activities. A number of reports have suggested that mHsp60 can stimulate human leukocytes and vascular endothelial cells to produce proinflammatory cytokines (17). Furthermore, it has been reported that mHsp60 has proapoptotic and antiapoptotic roles, depending on its cellular localization (18, 19). Finally, mHsp60 and mHsp10 were found to change their expression pattern in tumor cells (20, 21).The importance of mHsp60 for human cell function has been demonstrated through the autosomal dominant hereditary spastic paraplegia SPG13, a neurodegenerative disorder associated with two independent mutations in the gene encoding mHsp60 (22, 23). Recently, a large kindred including 23 patients suffering from MitCHAP-60 disease, an autosomal recessive neurodegenerative disorder, has been identified (24). Magnetic resonance imaging of the brains of the patients showed diffuse hypomyelination and leukodystrophy, in which myelin is not formed properly. The disease-causing mutation was identified to be a homozygous missense mutation in the human HSPD1 gene encoding the mHsp60 protein (24), namely D3G in the mature protein. Initial studies showed that, in contrast to wild-type mHsp60, the mutant, together with mHsp10, was not able to fully complement a deletion of the bacterial homologues, GroEL and GroES, in E. coli (24). The mechanism by which the D3G mutation may compromise the function of mHsp60 has not been reported. In this study, we suggest that the D3G mutation impedes the function of mHsp60 by entropic destabilization of the oligomeric structure of the molecule.     

The Biocultural Context of Very High Fertility among the Bekaa Bedouin

This research report explores some of the biocultural dimensions of maximum or near maximum fertility among Bedouin tribes in the Bekaa Valley, Lebanon. The Bedouin case substantiates that very high fertility (completed family size [CFS] greater than 8.0) is found among peripheral peoples in frontier situations generated by major political-economic shifts. While the Bedouin maintained high fertility (CFS > 6.5) for approximately sixty years (1899–1960), very high fertility—linked to greater historical reliance on agriculture—was of shorter duration (1934–60). Comparisons with other very high fertility populations indicate that, at the proximate level, maximum fertility is associated with early weaning, low rates of primary sterility, and high rates of marital stability. Results also point to low subadult mortality in Bedouin society. Low mortality is best attributed to the availability of modern medical care facilities and high-quality weaning foods.     

Serum Levels of Monocyte Chemoattractant Protein-1 and All-Cause and Cardiovascular Mortality among Patients with Coronary Artery Disease

Background

Monocyte chemoattractant protein-1 (MCP-1) is an important chemokine at multiple phases of atherosclerosis in animals, but human studies are few and inconsistent. The aim of this study is to investigate the association of serum MCP-1with all-cause and cardiovascular disease (CVD) mortality among coronary artery disease (CAD) patients and determine whether this biomarker can add secondary prognostic value to standard risk predictors.

Methods

MCP-1 was measured at baseline in 1411 CAD patients who were 40–85 years of age. Cox proportional hazards regression models were used to estimate the association of MCP-1 levels with death risk.

Results

During a median follow-up of 3.3 years, 117 deaths were recorded, 88 of which were due to CVD. The multivariable-adjusted hazard ratios across tertiles of MCP-1 were 1.51 (95% confidence intervals [CI] 0.89–2.58), 1.00, and 2.11 (95% CI 1.31–3.40) for all-cause mortality, and 1.50 (95% CI 0.80–2.81), 1.00, and 2.21 (95% CI 1.27–3.87) for CVD mortality. The addition of serum MCP-1 to the fully adjusted model increased the C-index by 0.009 (p<0.0001) for all-cause mortality and 0.008 (p<0.0001) for CVD mortality and significantly improved the predictive ability by 12.1% (P = 0.006) on all-cause mortality and 12.6% (P = 0.003) on CVD mortality using the net reclassification improvement method.

Conclusions

Both lower and higher MCP-1 levels are associated with an increased risk of all-cause and CVD mortality among CAD patients. More research is needed to confirm its clinical relevance.     

Hepcidin-25 in Diabetic Chronic Kidney Disease Is Predictive for Mortality and Progression to End Stage Renal Disease

Background

Anemia is common and is associated with impaired clinical outcomes in diabetic chronic kidney disease (CKD). It may be explained by reduced erythropoietin (EPO) synthesis, but recent data suggest that EPO-resistance and diminished iron availability due to inflammation contribute significantly. In this cohort study, we evaluated the impact of hepcidin-25—the key hormone of iron-metabolism—on clinical outcomes in diabetic patients with CKD along with endogenous EPO levels.

Methods

249 diabetic patients with CKD of any stage, excluding end-stage renal disease (ESRD), were enrolled (2003–2005), if they were not on EPO-stimulating agent and iron therapy. Hepcidin-25 levels were measured by radioimmunoassay. The association of hepcidin-25 at baseline with clinical variables was investigated using linear regression models. All-cause mortality and a composite endpoint of CKD progression (ESRD or doubling of serum creatinine) were analyzed by Cox proportional hazards models.

Results

Patients (age 67 yrs, 53% male, GFR 51 ml/min, hemoglobin 131 g/L, EPO 13.5 U/L, hepcidin-25 62.0 ng/ml) were followed for a median time of 4.2 yrs. Forty-nine patients died (19.7%) and forty (16.1%) patients reached the composite endpoint. Elevated hepcidin levels were independently associated with higher ferritin-levels, lower EPO-levels and impaired kidney function (all p<0.05). Hepcidin was related to mortality, along with its interaction with EPO, older age, greater proteinuria and elevated CRP (all p<0.05). Hepcidin was also predictive for progression of CKD, aside from baseline GFR, proteinuria, low albumin- and hemoglobin-levels and a history of CVD (all p<0.05).

Conclusions

We found hepcidin-25 to be associated with EPO and impaired kidney function in diabetic CKD. Elevated hepcidin-25 and EPO-levels were independent predictors of mortality, while hepcidin-25 was also predictive for progression of CKD. Both hepcidin-25 and EPO may represent important prognostic factors of clinical outcome and have the potential to further define “high risk” populations in CKD.     

Association of Sick Sinus Syndrome with Incident Cardiovascular Disease and Mortality: The Atherosclerosis Risk in Communities Study and Cardiovascular Health Study

Background

Sick sinus syndrome (SSS) is a common indication for pacemaker implantation. Limited information exists on the association of sick sinus syndrome (SSS) with mortality and cardiovascular disease (CVD) in the general population.

Methods

We studied 19,893 men and women age 45 and older in the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS), two community-based cohorts, who were without a pacemaker or atrial fibrillation (AF) at baseline. Incident SSS cases were validated by review of medical charts. Incident CVD and mortality were ascertained using standardized protocols. Multivariable Cox models were used to estimate the association of incident SSS with selected outcomes.

Results

During a mean follow-up of 17 years, 213 incident SSS events were identified and validated (incidence, 0.6 events per 1,000 person-years). After adjustment for confounders, SSS incidence was associated with increased mortality (hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.14–1.70), coronary heart disease (HR 1.72, 95%CI 1.11–2.66), heart failure (HR 2.87, 95%CI 2.17–3.80), stroke (HR 1.56, 95%CI 0.99–2.46), AF (HR 5.75, 95%CI 4.43–7.46), and pacemaker implantation (HR 53.7, 95%CI 42.9–67.2). After additional adjustment for other incident CVD during follow-up, SSS was no longer associated with increased mortality, coronary heart disease, or stroke, but remained associated with higher risk of heart failure (HR 2.00, 95%CI 1.51–2.66), AF (HR 4.25, 95%CI 3.28–5.51), and pacemaker implantation (HR 25.2, 95%CI 19.8–32.1).

Conclusion

Individuals who develop SSS are at increased risk of death and CVD. The mechanisms underlying these associations warrant further investigation.     

Left Ventricular Global Longitudinal Strain (GLS) Is a Superior Predictor of All-Cause and Cardiovascular Mortality When Compared to Ejection Fraction in Advanced Chronic Kidney Disease

BackgroundEchocardiographic global longitudinal strain (GLS) is increasingly recognised as a more effective technique than conventional ejection fraction (EF) in detecting subtle changes in left ventricular (LV) function. This study investigated the prognostic value of GLS over EF in patients with advanced Chronic Kidney Disease (CKD).MethodsThe study included 183 patients (57% male, 63% on dialysis) with CKD stage 4, 5 and 5Dialysis (D). 112 (61%) of patients died in a follow up of 7.8 ± 4.4 years and 41% of deaths were due to cardiovascular (CV) disease. GLS was calculated using 2-dimensional speckle tracking and EF was measured using Simpson’s biplane method. Cox proportional hazard models were used to assess the association of measures of LV function and all- cause and CV mortality.ResultsThe mean GLS at baseline was -13.6 ± 4.3% and EF was 45 ± 11%. GLS was a significant predictor of all-cause [Hazard Ratio (HR) 1.09 95%; Confidence Interval (CI) 1.02–1.16; p = 0.01] and CV mortality (HR 1.16 95%; CI 1.04–1.30; p = 0.008) following adjustment for relevant clinical variables including LV mass index (LVMI) and EF. GLS also had greater predictive power for both all- cause and CV mortality compared to EF. Impaired GLS (>-16%) was associated with a 5.6-fold increased unadjusted risk of CV mortality in patients with preserved EF.ConclusionsIn this cohort of patients with advanced CKD, GLS is a more sensitive predictor of overall and CV mortality compared to EF. Studies of larger populations in CKD are required to confirm that GLS provides additive prognostic value in patients with preserved EF.     

The Serotonin Transporter Undergoes Constitutive Internalization and Is Primarily Sorted to Late Endosomes and Lysosomal Degradation

The serotonin transporter (SERT) plays a critical role in regulating serotonin signaling by mediating reuptake of serotonin from the extracellular space. The molecular and cellular mechanisms controlling SERT levels in the membrane remain poorly understood. To study trafficking of the surface resident SERT, two functional epitope-tagged variants were generated. Fusion of a FLAG-tagged one-transmembrane segment protein Tac to the SERT N terminus generated a transporter with an extracellular epitope suited for trafficking studies (TacSERT). Likewise, a construct with an extracellular antibody epitope was generated by introducing an HA (hemagglutinin) tag in the extracellular loop 2 of SERT (HA-SERT). By using TacSERT and HA-SERT in antibody-based internalization assays, we show that SERT undergoes constitutive internalization in a dynamin-dependent manner. Confocal images of constitutively internalized SERT demonstrated that SERT primarily co-localized with the late endosomal/lysosomal marker Rab7, whereas little co-localization was observed with the Rab11, a marker of the “long loop” recycling pathway. This sorting pattern was distinct from that of a prototypical recycling membrane protein, the β₂-adrenergic receptor. Furthermore, internalized SERT co-localized with the lysosomal marker LysoTracker and not with transferrin. The sorting pattern was further confirmed by visualizing internalization of SERT using the fluorescent cocaine analog JHC1-64 and by reversible and pulse-chase biotinylation assays showing evidence for lysosomal degradation of the internalized transporter. Finally, we found that SERT internalized in response to stimulation with 12-myristate 13-acetate co-localized primarily with Rab7- and LysoTracker-positive compartments. We conclude that SERT is constitutively internalized and that the internalized transporter is sorted mainly to degradation.