UNASSIGNED: The survival benefit of residual kidney function (RKF) in patients on hemodialysis is presumably due to enhanced fluid management and solute clearance. However, data are lacking on the association of renal urea clearance (CLurea) with specific causes of death.
UNASSIGNED: We conducted a longitudinal cohort study of 39,623 adults initiating thrice-weekly in-center hemodialysis from 2007 to 2011 and had data on renal CLurea and urine volume. Multivariable cause-specific proportional hazards model was used to examine the associations between baseline RKF and cause-specific mortality, including sudden cardiac death (SCD), non-SCD cardiovascular death (CVD), and non-CVD. Restricted cubic splines were fitted for change in RKF over 6 months after initiating hemodialysis.
UNASSIGNED: Among 39,623 patients with data on baseline renal CLurea and urine volume, there was a significant trend toward a higher mortality risk across lower RKF levels, irrespective of cause of death in a case-mix adjustment model (Ptrend < 0.05). Adjustment for ultrafiltration rate (UFR) slightly attenuated the association between low renal CLurea and high cause-specific mortality, whereas adjustment for highest potassium did not have substantial effect. Among 12,169 patients with data on change in RKF, a 6-month decline in renal CLurea showed graded associations with SCD, non-SCD CVD, and non-CVD risk, whereas the graded associations between faster 6-month decline in urine output and higher death risk were clear only for SCD and non-CVD.
UNASSIGNED: Lower RKF and loss of RKF were associated with higher cause-specific mortality among patients initiating thrice-weekly in-center hemodialysis.

BACKGROUND: There is an increasing amount of evidence suggesting multiple fatal complications in takotsubo syndrome; however, findings on the long-term outcome are scarce and show inconsistent evidence.
METHODS: This is a single center study of long-term prognosis in takotsubo patients admitted to the Klinik Ottakring, Vienna, Austria, from September 2006 to August 2019. We investigated the clinical features, prognostic factors and outcome of patients with takotsubo syndrome. Furthermore, survivors and non-survivors and patients with a different cause of death were compared.
RESULTS: Overall, 147 patients were included in the study and 49 takotsubo patients (33.3%) died during the follow-up, with a median of 126 months. The most common cause of death was a non-cardiac cause (71.4% of all deaths), especially malignancies (26.5% of all deaths). Moreover, non-survivors were older and more often men with more comorbidities (chronic kidney disease, malignancy). Patients who died because of cardiovascular disease were older and more often women than patients who died due to non-cardiovascular cause. Adjusted analysis showed no feature of an independent predictor of cardiovascular mortality for takotsubo patients. Female gender (HR = 0.32, CI: 0.16-0.64, p < 0.001), cancer (HR = 2.35, CI: 1.15-4.8, p = 0.019) and chronic kidney disease (HR = 2.61, CI: 1.11-6.14, p = 0.028) showed to be independent predictors of non-cardiovascular mortality.
CONCLUSIONS: Long-term prognosis of takotsubo patients is not favorable, mainly due to noncardiac comorbidities. Hence, consequent outpatient care in regular intervals after a takotsubo event based on risk factor control and early detection of malignancies seems justified.

UNASSIGNED: Chronic kidney disease (CKD) is associated with an elevated risk of all-cause mortality, with cardiovascular death being extensively investigated. However, non-cardiovascular mortality represents the biggest percentage, showing an evident increase in recent years. Klotho is a gene highly expressed in the kidney, with a clear influence on lifespan. Low levels of Klotho have been linked to CKD progression and adverse outcomes. Single nucleotide polymorphisms (SNPs) of the Klotho gene have been associated with several diseases, but studies investigating the association of Klotho SNPs with non-cardiovascular death in CKD populations are lacking.
UNASSIGNED: The main aim of this study was to assess whether 11 Klotho SNPs were associated with non-cardiovascular death in a subpopulation of the National Observatory of Atherosclerosis in Nephrology (NEFRONA) study (n = 2185 CKD patients).
UNASSIGNED: After 48 months of follow-up, 62 cardiovascular deaths and 108 non-cardiovascular deaths were recorded. We identified a high non-cardiovascular death risk combination of SNPs corresponding to individuals carrying the most frequent allele (G) at rs562020, the rare allele (C) at rs2283368 and homozygotes for the rare allele (G) at rs2320762 (rs562020 GG/AG + rs2283368 CC/CT + rs2320762 GG). Among the patients with the three SNPs genotyped (n = 1016), 75 (7.4%) showed this combination. Furthermore, 95 (9.3%) patients showed a low-risk combination carrying all the opposite genotypes (rs562020 AA + rs2283368 TT + rs2320762 GT/TT). All the other combinations [n = 846 (83.3%)] were considered as normal risk. Using competing risk regression analysis, we confirmed that the proposed combinations are independently associated with a higher {hazard ratio [HR] 3.28 [confidence interval (CI) 1.51-7.12]} and lower [HR 6 × 10-6 (95% CI 3.3 × 10-7-1.1 × 10-5)] risk of suffering a non-cardiovascular death in the CKD population of the NEFRONA cohort compared with patients with the normal-risk combination.
UNASSIGNED: Determination of three SNPs of the Klotho gene could help in the prediction of non-cardiovascular death in CKD.

Heart failure (HF) patients are at high-risk of cardiovascular (CV) events, including CV death. Nonetheless, a substantial proportion of these patients die from non-CV causes. Identifying patients at higher risk for each individual event may help selecting patients for clinical trials and tailoring cardiovascular therapies. The aims of the present study are to: (i) characterize patients according to CV vs. non-CV death; (ii) develop models for the prediction of the respective events; (iii) assess the models\' performance to differentiate CV from non-CV death.
This study included 2309 patients with HF from the BIOSTAT-CHF (a systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure) study. Competing-risk models were used to assess the best combination of variables associated with each cause-specific death. Results were validated in an independent cohort of 1738 HF patients. The best model to predict CV death included low blood pressure, estimated glomerular filtration rate ≤ 60 mL/min, peripheral oedema, previous HF hospitalization, ischaemic HF, chronic obstructive pulmonary disease, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP), and troponin (c-index = 0.73). The non-CV death model incorporated age > 75 years, anaemia and elevated NT-proBNP (c-index = 0.71). Both CV and non-CV death rose by quintiles of the risk scores; yet these models allowed the identification of patients in whom absolute CV death rates clearly outweigh non-CV death ones. These findings were externally replicated, but performed worse in a less severely diseased population.
Risk models for predicting CV and non-CV death allowed the identification of patients at higher absolute risk of dying from CV causes (vs. non-CV ones). Troponin helped in predicting CV death only, whereas NT-proBNP helped in the prediction of both CV and non-CV death. These findings can be useful both for tailoring therapies and for patient selection in HF trials in order to attain CV event enrichment.

Better management of heart failure (HF) over the past two decades has improved survival, mainly by reducing the incidence of death due to cardiovascular (CV) causes. Deaths due to non-CV causes, particularly cancer, may be increasing. This study explored the modes of death of consecutive patients who attended a HF clinic over 17 years.
A total of 935 deaths were ascertained from 2002 to 2018 among 1876 patients (mean age 65.8 ± 12.5 years, 75% men, left ventricular ejection fraction < 50%) admitted to our HF clinic. Median follow-up was 4.2 years [1.9-7.8]. Mode of death was curated from patient health records and verified by the Catalan and Spanish health system databases. Trends for every mode of death were assessed by polynomial regression. Two trends were observed: a significant reduction in sudden death (P = 0.03) without changes in HF progression as mode of death (P = 0.26), and a significant increase in non-CV modes of death (P < 0.001). Non-CV deaths accounted for 17.4% of deaths in 2002 and 65.8% of deaths in 2018. A total 138 deaths were due to cancer (37% of non-CV deaths). A significant trend was observed towards a progressive increase in cancer deaths over time (P = 0.002). The main mode of cancer mortality was lung cancer.
The modes of death in HF have shifted over the last two decades. Patients with HF die less due to sudden death and more due to non-CV causes, mainly cancer. Whether HF triggers cancer, or cancer develops in HF survivors, deserves further insight.

Heart failure (HF) with preserved ejection fraction (HFpEF) represents half of HF patients, who are more likely older, women, and hypertensive. Mortality rates in HFpEF are higher compared with age- and comorbidity-matched non-HF controls and lower than in HF with reduced ejection fraction (HFrEF); the majority (50-70%) are cardiovascular (CV) deaths. Among CV deaths, sudden death (SD) (~ 35%) and HF-death (~ 20%) are the leading cardiac modes of death; however, proportionally, CV deaths, SD, and HF-deaths are lower in HFpEF, while non-CV deaths constitute a higher proportion of deaths in HFpEF (30-40%) than in HFrEF (~ 15%). Importantly, the underlying mechanism of SD has not been clearly elucidated and non-arrhythmic SD may be more prominent in HFpEF than in HFrEF. Furthermore, there is no specific strategy for identifying high-risk patients, probably due to wide heterogeneity in presentation and pathophysiology of HFpEF and a plethora of comorbidities in this population. Thus, the management of HFpEF remains problematic due to paucity of data on the clinical benefits of current therapies, which focus on symptom relief and reduction of HF-hospitalization by controlling fluid retention and managing risk-factors and comorbidities. Matching a specific pathophysiology or mode of death with available and novel therapies may improve outcomes in HFpEF. However, this still remains an elusive target, as we need more information on determinants of SD. Implantable cardioverter-defibrillators (ICDs) have changed the landscape of SD prevention in HFrEF; if ICDs are to be applied to HFpEF, there must be a coordinated effort to identify and select high-risk patients.

BACKGROUND: Little information is available on non-cardiovascular (CV) death in acute heart failure (AHF) patients. The present study determined the incidence, time course, and factors associated with long-term non-CV death in AHF patients in a real-world setting.
METHODS: The ATTEND registry, a nationwide, prospective observational multicenter cohort study, included 4842 consecutive patients hospitalized for AHF. The primary endpoint of the present study was non-CV death.
RESULTS: Median follow-up duration from admission was 513 (range, 385-778) days. Over the study period, 1183 patients died; 356 deaths (30.1%) were non-CV related. The proportion of non-CV deaths increased in the later follow-up phase (0-180days, 26.7%; 181-360days, 38.4%; >360days, 36.6%, p<0.001). After adjustment for all variables at baseline, age (hazard ratio [HR] 1.6 per decade, p<0.001) and non-cardiac comorbidities including chronic obstructive pulmonary disease (HR 1.58, p=0.003), history of stroke (HR 1.44, p=0.011), renal insufficiency (HR 1.07, per 10ml/min/1.73m2 decrease in estimated glomerular filtration, p=0.015), and hemoglobin (HR 1.15 per 1.0g/dl decrease, p<0.001) were strongly associated with non-CV death. Other predictors included ischemic etiology (HR 1.33, p=0.023), prior hospitalization for heart failure (HR 1.34, p=0.017), C-reactive protein (HR 1.04, p<0.001), and statin use (HR 0.70, p=0.016).
CONCLUSIONS: The incidence of non-CV death was high in patients with AHF, accounting for 30% of long-term mortality. Furthermore, the proportion of non-CV death increased in the later follow-up phase. Better understanding of non-CV death and more comprehensive treatment of non-CV comorbidities are vital to further improving prognosis in AHF patients.

The ankle-brachial index (ABI) is the ratio of the ankle versus brachial systolic blood pressure. ABI of <0.90 indicates the presence of peripheral arterial disease. Some studies indicated that ABI may correlate with the all-cause mortality. The aim of this study was to assess the prognostic significance of ABI of <0.90 as such predictor of all-cause mortality. In addition, we wished to test the association between ABI and cardiovascular or non-cardiovascular mortality. To this end, we carried out a systematic review of the studies published in MEDLINE that reported both ABI and all-cause mortality. The endpoint of interest was the all-cause mortality, including death from coronary disease, stroke, or other causes. Ten studies, with a total of 22,705 patients, were included in this review. ABI of <0.90 was proved to be associated with an increased risk of all-cause mortality [odds ratio 2.74 (95 % confidence interval 2.03-3.68) and number needed to harm 1.66], as well as with cardiovascular [i.e., death from coronary disease or stroke; respectively, 3.23 (1.98-5.29) and 1.26] and non-cardiovascular mortality [respectively, 2.23 (1.40-3.55) and 1.29]. In conclusion, ABI of <0.9 is useful as a prognostic factor for all-cause mortality.

BACKGROUND: The relative and absolute risks of outcomes other than all-cause death (ACD) attributable to atrial fibrillation (AF) stratified age have not been sufficiently investigated.
METHODS: A prospective study of 23,634 community dwellers aged 40 years or older without organic cardiovascular disease (AF=335, non-AF=23,299) was conducted. Multivariate-adjusted rates, rate ratios (RRs) and excess deaths (EDs) for ACD, cardiovascular death (CVD) and non-cardiovascular death (non-CVD), and sex- and age-adjusted RR and ED in middle-aged (40 to 69) and elderly (70 years or older) for ACD, CVD, non-CVD, sudden cardiac death (SCD), stroke-related death (Str-D), neoplasm-related death (NPD), and infection-related death (IFD) attributable to AF were estimated using Poisson regression.
RESULTS: Multivariate-adjusted analysis revealed that AF significantly increased the risk of ACD (RR [95% confidence interval]:1.70 [1.23-2.95]) and CVD (3.86 [2.38-6.27]), but not non-CVD. Age-stratified analysis revealed that AF increased the risk of Str-D in middle-aged (14.5 [4.77-44.3]) and elderly individuals (4.92 [1.91-12.7]), SCD in elderly individuals (3.21 [1.37-7.51]), and might increase the risk of IFD in elderly individuals (2.02 [0.80-4.65], p=0.098). The RR of CVD was higher in middle-aged versus elderly individuals (RRs, 6.19 vs. 3.57) but the absolute risk difference was larger in elderly individuals (EDs: 7.6 vs. 3.0 per 1000 person-years).
CONCLUSIONS: Larger absolute risk differences for ACD and CVD attributable to AF among elderly people indicate that the absolute burden of AF is higher in elderly versus middle-aged people despite the relatively small RR.