Everolimus and long-term decline in renal function after liver transplantation: real-life experience with measured GFR.

Switching from calcineurin-inhibitors (CNI) to everolimus >6-12-months after liver transplantation (LT) seems inefficient in improving renal function, but whether everolimus halts further renal-function decline compared to low-dose CNI remains unclear. In a retrospective single-center study of everolimus after LT (2008-2016) with routine measured glomerular filtration rates (mGFR; 51Cr-EDTA- or iohexol clearance), we compared by propensity-score matching everolimus therapy to low-dose CNI therapy. The study comprised 36 patients with everolimus introduced on average 22 months post-LT (range 2-105 months, median follow-up 3.4 years), and 36 matched controls. Everolimus introduction was associated with a mean improvement in mGFR of 7 mL/min up to 1 year (p = .003), restricted to patients switched <1-year post-transplant and at tacrolimus trough levels >5 ng/mL. The differences between the everolimus group and controls in delta-mGFR from baseline to 1 year (7.3 vs 4.3 mL/min, p = .25) or 1-year to last follow-up (-0.8 vs -0.2 mL/min/year, p = .71) were non-significant. Proportions with mGFR decline >3 mL/min/year were similar between groups (11% and 14%, p = 1.00). Everolimus was stopped in three patients (8%), and acute rejection occurred in 17%. In conclusion, despite an early improvement in renal function after everolimus introduction, we found no evidence that everolimus halts the long-term mGFR decline compared to continued low-dose CNI therapy. Due to retrospective design, small sample size and heterogenous characteristics, definite conclusions require prospective studies.

ST segment depression on 24-hour electrocardiography predicts incident atrial fibrillation in two population-based cohorts.

Aims: ST-depression at 24hECG has not been studied in relation to atrial fibrillation (AF) risk. We aimed to determine whether ST-depression at 24hECG was associated with incident AF in two Swedish population-based cohorts - a sub-cohort of the Malmö Diet and Cancer study (MDCS), and the cohort 'Men born in 1914', and to determine whether 24hECG could be used to predict AF development. Methods and results: There were 378 acceptable 24hECG recordings in the MDCS (mean age 64.5 years, 43% men) and 394 acceptable recordings in 'Men born in 1914' (mean age 68.8 years). Incidence of AF was monitored using national registers of hospitalizations and outpatient visits in Sweden. Mean follow-up ± SD (cumulative incidence) was 10.4 ± 2 years (11.3%) in MDCS, and 10.9 ± 4 years (7.3%) in 'Men born in 1914'. ST-depressions were independently associated with incident AF; hazard ratio (HR) (95% CI) 2.41 (1.29-4.50, P = 0.006) and 2.28 (1.05-4.95, P = 0.038) after adjustment [age, sex, height, weight, systolic blood pressure, smoking, anti-hypertensive drugs, LDL/total cholesterol, and HOMA-IR (in MDCS)]. AF incidence was substantially lower in individuals who had neither ST-depressions or high supraventricular activity (SVA, negative predictive value 0.97 and 0.94, in MDCS and 'Men born in 1914', respectively), and similar in men and women. Conclusion: ST-depression at 24h-ECG is independently associated with incident AF, and incidence is substantially lower in individuals with neither ST-depression or high SVA. 24hECG can be used not only to diagnose AF but also to identify individuals at high and low AF risk.

Orosomucoid, Carotid Plaque, and Incidence of Stroke.

BACKGROUND AND PURPOSE: Orosomucoid (α-1-acid glycoprotein) is an acute-phase protein that has been implicated in anti-inflammatory, immunomodulating, and angiogenic pathways. Orosomucoid has also been associated with coronary disease and stroke. The relationship between orosomucoid, carotid plaque, and stroke incidence were explored in this study. METHODS: Plasma levels of orosomucoid were assessed in 4285 subjects (39.8% men; mean age 57.5±5.9 years) without cardiovascular disease, who participated in the Malmö Diet and Cancer Study, between 1991 and 1994. The right carotid artery was examined for plaque using B-mode ultrasound examination. Incidence of stroke was followed up during a median follow-up time of 17.7 years. RESULTS: Carotid plaque was present in 43.5% at baseline. Orosomucoid was significantly higher in subjects with carotid plaque (mean±SD: 0.72±0.22 versus 0.69±0.20 g/L; P<0.001). A total of 234 subjects were diagnosed with ischemic stroke during follow-up. Orosomucoid was associated with ischemic stroke after adjustment for risk factors, with hazard ratio 1.48 (95% confidence interval, 1.02-2.16) comparing the third versus first tertile. In subjects with plaque and belonging to the top tertile of orosomucoid, the hazard ratio was 2.07 (95% confidence interval, 1.38-3.11) compared with those without plaque and with orosomucoid in the first and second tertiles, after adjustment for C-reactive protein and other risk factors. CONCLUSIONS: Elevated levels of orosomucoid are associated with increased occurrence of carotid plaque and increased incidence of ischemic stroke. The combination of high orosomucoid and carotid plaque substantially increase the risk of stroke.

Plasma natriuretic peptides and incidence of subtypes of ischemic stroke.

BACKGROUND AND PURPOSE: Natriuretic peptides predict poor outcomes in cardiovascular disease. However, the knowledge of their relationship to stroke is limited and prospective studies from the general population are few. The purpose of this study was to explore the relationship between N-terminal pro-brain natriuretic peptide (NT-proBNP) and midregional pro-atrial natriuretic peptide (MR-proANP) plasma levels and the risk for ischemic stroke and its subtypes. METHODS: NT-proBNP and MR-proANP were measured in fasting blood samples from 4,862 subjects (40.2% men, mean age 57.5 ± 6.0 years) without cardiovascular disease from the Malmö Diet and Cancer Study, a prospective, population-based study in Sweden. Incidence of ischemic stroke was monitored over a mean follow-up of 14.9 ± 3.0 years. Stroke cases were etiologically classified according to the TOAST classification. Cox proportional-hazards regression was used to study the incidence of stroke in relationship to NT-proBNP and MR-proANP. RESULTS: During follow-up, 227 had a first-ever ischemic stroke (large-artery atherosclerosis, n = 35; cardioembolic stroke, n = 44; small-artery occlusion, n = 80; undetermined cause, n = 68). In the age- and sex-adjusted model, only NT-proBNP was associated with total ischemic stroke. This association was completely explained by an increased incidence of cardioembolic stroke. Adjusted for cardiovascular risk factors (age, sex, hypertension, diabetes, smoking, body mass index and low-density lipoprotein cholesterol), the hazard ratios (HRs, 95% confidence interval, 95% CI) for cardioembolic stroke were 1.00 (reference), 1.42 (0.34-6.00), 2.79 (0.77-10.12) and 5.64 (1.66-19.20), respectively, for the 1st, 2nd, 3rd and 4th quartiles of NT-proBNP. The corresponding HRs (95% CIs) for quartiles of MR-proANP were 1.00 (reference), 1.83 (0.55-6.14), 1.20 (0.33-4.34) and 3.96 (1.31-11.99), respectively. In total, 335 (6.9%) subjects were diagnosed with atrial fibrillation during follow-up. Among the cardioembolic stroke cases, 30% were diagnosed with atrial fibrillation before the stroke event and another 36% within 6 months after the stroke. Of the cardioembolic stroke cases with atrial fibrillation, 59% were in the top quartile of NT-proBNP, 69% in the top quartile of MR-proANP and 79% were either in the top quartile of NT-proBNP or in the top quartile of MR-proANP. CONCLUSION: High plasma levels of NT-proBNP and MR-proANP are associated with a substantially increased risk of cardioembolic stroke, but not with other subtypes of ischemic stroke. The results suggest that assessment of stroke risk, including electrocardiography, is warranted in subjects with high NT-proBNP or MR-proANP.

Risk of Stroke in Patients With Atrial Fibrillation Is Associated With Stroke in Siblings: A Nationwide Study.

Background It remains unclear whether heritable factors can contribute to risk stratification for ischemic stroke in patients with atrial fibrillation (AF). We examined whether having a sibling with ischemic stroke was associated with increased risk of ischemic stroke and mortality in patients with AF. Methods and Results In this nationwide study of the Swedish population, patients with AF and their siblings were identified from the Swedish patient registers and the Swedish MGR (Multi-Generation Register). Ischemic stroke events were retrieved from the Swedish patient registers and CDR (Cause of Death Register). Risk of ischemic stroke was compared between patients with AF with and without a sibling affected by ischemic stroke, AF, or both ischemic stroke and AF. The total study population comprised 113 988 subjects (mean age, 60±12 years) diagnosed with AF between 1989 and 2012. In total, 11 709 of them were diagnosed with a first ischemic stroke and 20 097 died during a mean follow-up time of 5.5 years for ischemic stroke and 5.9 years for mortality. After adjustment for covariates having a sibling with ischemic stroke, or both ischemic stroke and AF, was associated with increased risk of ischemic stroke (hazard ratio, 1.31; 95% CI, 1.23-1.40 or hazard ratio, 1.36; 95% CI, 1.24-1.49, respectively). Furthermore, ischemic stroke in a sibling was associated with all-cause mortality (hazard ratio, 1.09; 95% CI, 1.05-1.14). In contrast, the risk of stroke was only marginally increased for patients with AF with a spouse affected by ischemic stroke. Conclusions Having a sibling affected by ischemic stroke confers an increased risk of ischemic stroke and death independently of traditional risk factors in patients with AF.

Increased vascular endothelial growth factor D is associated with atrial fibrillation and ischaemic stroke.

OBJECTIVE: Vascular endothelial growth factor D (VEGF-D) has important functions in lymphangiogenesis and angiogenesis. High plasma levels of VEGF-D have been associated with incidence of heart failure. The association of VEGF-D with atrial fibrillation (AF) and stroke is unclear and we hypothesised that VEGF-D could also be associated with incidence of AF and ischaemic stroke. METHODS: VEGF-D was measured in fasting blood samples of 4689 subjects (40% men) without a history of AF from the Malmö Diet and Cancer Study, a prospective, population-based study in Sweden. Median age was 58 years (range 46-68). Cox regression analyses, adjusted for multiple risk factors, was used to assess AF and ischaemic stroke risk in relation to VEGF-D levels. RESULTS: During a median follow-up time of 20.6 years, there were 637 cases of incident AF and 322 cases of first ischaemic stroke. After adjustment, VEGF-D was significantly associated with AF (HR 1.13(95% CI 1.04 to 1.23) per 1 SD increase) and ischaemic stroke (HR 1.14(95% CI 1.02 to 1.28) per 1 SD). The association with ischaemic stroke was explained by an increased incidence of AF-related stroke. HRs per 1 SD were 1.34 (95% CI 1.04 to 1.71) for AF-related ischaemic stroke and 1.04 (95% CI 0.90 to 1.19) for ischaemic stroke without AF. CONCLUSIONS: Increased VEGF-D concentrations were associated with AF and ischaemic stroke. The relationship with ischaemic stroke was more pronounced in subjects with a diagnosis of AF.

Profiling of the plasma proteome across different stages of human heart failure.

Heart failure (HF) is a major public health problem characterized by inability of the heart to maintain sufficient output of blood. The systematic characterization of circulating proteins across different stages of HF may provide pathophysiological insights and identify therapeutic targets. Here we report application of aptamer-based proteomics to identify proteins associated with prospective HF incidence in a population-based cohort, implicating modulation of immunological, complement, coagulation, natriuretic and matrix remodeling pathways up to two decades prior to overt disease onset. We observe further divergence of these proteins from the general population in advanced HF, and regression after heart transplantation. By leveraging coronary sinus samples and transcriptomic tools, we describe likely cardiac and specific cellular origins for several of the proteins, including Nt-proBNP, thrombospondin-2, interleukin-18 receptor, gelsolin, and activated C5. Our findings provide a broad perspective on both cardiac and systemic factors associated with HF development.

Pro-atrial natriuretic peptide and prediction of atrial fibrillation and stroke: The Malmö Preventive Project.

Background The increasing prevalence of atrial fibrillation and novel therapeutic tools to prevent cardioembolic stroke has increased the need for risk markers. Objectives This study explored the relationship between the midregional sequence of pro-atrial natriuretic peptide (MR-proANP) levels with the risk of atrial fibrillation and stroke, and whether measurement of MR-proANP improves the prediction of these outcomes. Methods MR-proANP was measured in fasting blood samples of 5130 subjects (69% men, mean age 69.2 ± 6.2 years) without a history of atrial fibrillation or stroke from the general population. The incidence of atrial fibrillation and stroke was monitored over a median follow-up of 5.6 years. C-statistics and net reclassification improvement was used to assess the predictive ability of MR-proANP in addition to conventional risk factors. Results Log-normalized MR-proANP was significantly associated with the incidence of atrial fibrillation ( n = 362; hazard ratio (HR); 95% confidence interval (CI) per 1 standard deviation (SD) 2.05, 1.86-2.27) and stroke from all causes ( n = 195; HR 1.30; 95% CI 1.12-1.50). The HR for stroke events related to atrial fibrillation was 1.79 (95% CI 1.25-2.58) per 1 SD. MR-proANP significantly improved the prediction of atrial fibrillation when added to a risk score of conventional risk factors (C statistic 0.69 vs. 0.75), mainly by down-classifying subjects who did not develop atrial fibrillation. A smaller improvement in predictive ability was observed for stroke (C statistic 0.66 vs. 0.68). Conclusion High plasma levels of MR-proANP are associated with the incidence of atrial fibrillation and stroke in the middle-aged and elderly population. MR-proANP may be useful to identify individuals with an increased risk of atrial fibrillation.