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  • Klionsky, Daniel J., et al. (författare)
  • Guidelines for the use and interpretation of assays for monitoring autophagy
  • 2012
  • Ingår i: Autophagy. - : Landes Bioscience. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
  • Forskningsöversikt (refereegranskat)abstract
    • In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
  • Bandak, Ghassan, et al. (författare)
  • Hyperkalemia after initiating renin-angiotensin system blockade : The Stockholm creatinine measurements (SCREAM) project
  • 2017
  • Ingår i: Journal of the American Heart Association. - : WILEY. - 2047-9980 .- 2047-9980. ; 6:7
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Concerns about hyperkalemia limit the use of angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs), but guidelines conflict regarding potassium-monitoring protocols. We quantified hyperkalemia monitoring and risks after ACE-I/ARB initiation and developed and validated a hyperkalemia susceptibility score.METHODS AND RESULTS: We evaluated 69 426 new users of ACE-I/ARB therapy in the Stockholm Creatinine Measurements (SCREAM) project with medication initiation from January 1, 2007 to December 31, 2010, and follow-up for 1 year thereafter. Three fourths (76%) of SCREAM patients had potassium checked within the first year. Potassium >5 and >5.5 mmol/L occurred in 5.6% and 1.7%, respectively. As a comparison, we propensity-matched new ACE-I/ARB users to 20 186 new β-blocker users in SCREAM: 64% had potassium checked. The occurrence of elevated potassium levels was similar between new β-blocker and ACE-I/ARB users without kidney disease; only at estimated glomerular filtration rate <60 mL/min per 1.73 m(2) were risks higher among ACE-I/ARB users. We developed a hyperkalemia susceptibility score that incorporated estimated glomerular filtration rate, baseline potassium level, sex, diabetes mellitus, heart failure, and the concomitant use of potassium-sparing diuretics in new ACE-I/ARB users; this score accurately predicted 1-year hyperkalemia risk in the SCREAM cohort (area under the curve, 0.845, 95% CI: 0.840-0.869) and in a validation cohort from the US-based Geisinger Health System (N=19 524; area under the curve, 0.818, 95% CI: 0.794-0.841), with good calibration.CONCLUSIONS: Hyperkalemia within the first year of ACE-I/ARB therapy was relatively uncommon among people with estimated glomerular filtration rate >60 mL/min per 1.73 m(2), but rates were much higher with lower estimated glomerular filtration rate. Use of the hyperkalemia susceptibility score may help guide laboratory monitoring and prescribing strategies.
  • Bank, Ingrid E. M., et al. (författare)
  • Prevalence and Clinical Significance of Diabetes in Asian Versus White Patients With Heart Failure
  • 2017
  • Ingår i: JACC. Heart failure. - : ELSEVIER SCI LTD. - 2213-1779 .- 2213-1787. ; 5:1, s. 14-24
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES The study sought to compare the prevalence, clinical correlates and prognostic impact of diabetes in Southeast Asian versus white patients with heart failure (HF) with preserved or reduced ejection fraction. BACKGROUND Diabetes mellitus is common in HF and is associated with impaired prognosis. Asia is home to the majority of the worlds diabetic population, yet data on the prevalence and clinical significance of diabetes in Asian patients with HF are sparse, and no studies have directly compared Asian and white patients. METHODS Two contemporary population-based HF cohorts were combined: from Singapore (n 1,002, median [25th to 75th percentile] age 62 [54 to 70] years, 76% men, 19.5% obesity) and Sweden (n =19,537, 77 [68 to 84] years, 60% men, 24.8% obesity). The modifying effect of ethnicity on the relationship between diabetes and clinical correlates or prognosis (HF hospitalization and all-cause mortality) was examined using interaction terms. RESULTS Diabetes was present in 569 (57%) Asian patients versus 4,680 (24%) white patients (p amp;lt; 0.001). Adjusting for clinical covariates, obesity was more strongly associated with diabetes in white patients (odds ratio [OR]: 3.45;. 95% confidence interval [CI]: 2.86 to 4.17) than in Asian patients (OR: 1.82; 95% CI: 1.13 to 2.96; P-interaction = 0.026). Diabetes was more strongly associated with increased HF hospitalization and all-cause mortality in Asian patients (hazard ratio: 1.50; 95% CI: 1.21 to 1.87) than in white patients (hazard ratio: 1.29; 95% CI: 1.22 to 1.36; P-interaction = 0.045). CONCLUSIONS Diabetes was 3-fold more common in Southeast Asian compared to white patients with HF, despite younger age and less obesity, and more strongly associated with poor outcomes in Asian patients than white patients. These results underscore the importance of ethnicity-tailored aggressive strategies to prevent diabetes and its complications. (C) 2017 by the American College of Cardiology Foundation.
  • Bilchick, K. C., et al. (författare)
  • Seattle Heart Failure and Proportional Risk Models Predict Benefit From Implantable Cardioverter-Defibrillators
  • 2017
  • Ingår i: Journal of the American College of Cardiology. - : ELSEVIER SCIENCE INC. - 0735-1097 .- 1558-3597. ; 69:21, s. 2606-2618
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND Recent clinical trials highlight the need for better models to identify patients at higher risk of sudden death. OBJECTIVES The authors hypothesized that the Seattle Heart Failure Model (SHFM) for overall survival and the Seattle Proportional Risk Model (SPRM) for proportional risk of sudden death, including death from ventricular arrhythmias, would predict the survival benefit with an implantable cardioverter-defibrillator (ICD). METHODS Patients with primary prevention ICDs from the National Cardiovascular Data Registry (NCDR) were compared with control patients with heart failure (HF) without ICDs with respect to 5-year survival using multivariable Cox proportional hazards regression. RESULTS Among 98,846 patients with HF (87,914 with ICDs and 10,932 without ICDs), the SHFM was strongly associated with all-cause mortality (p < 0.0001). The ICD-SPRM interaction was significant (p < 0.0001), such that SPRM quintile 5 patients had approximately twice the reduction in mortality with the ICD versus SPRM quintile 1 patients (adjusted hazard ratios [HR]: 0.602; 95% confidence interval [CI]: 0.537 to 0.675 vs. 0.793; 95% CI: 0.736 to 0.855, respectively). Among patients with SHFM-predicted annual mortality <= 5.7%, those with a SPRM-predicted risk of sudden death below the median had no reduction in mortality with the ICD (adjusted ICD HR: 0.921; 95% CI: 0.787 to 1.08; p = 0.31), whereas those with SPRM above the median derived the greatest benefit (adjusted HR: 0.599; 95% CI: 0.530 to 0.677; p < 0.0001). CONCLUSIONS The SHFM predicted all-cause mortality in a large cohort with and without ICDs, and the SPRM discriminated and calibrated the potential ICD benefit. Together, the models identified patients less likely to derive a survival benefit from primary prevention ICDs. (J Am Coll Cardiol 2017;69:2606-18) (C) 2017 by the American College of Cardiology Foundation.
  • Chen, Xiaojing, et al. (författare)
  • Age-dependent differences in clinical phenotype and prognosis in heart failure with mid-range ejection compared with heart failure with reduced or preserved ejection fraction
  • 2019
  • Ingår i: Clinical Research in Cardiology. - : Springer. - 1861-0684 .- 1861-0692. ; 108:12, s. 1394-1405
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: HFmrEF has been recently proposed as a distinct HF phenotype. How HFmrEF differs from HFrEF and HFpEF according to age remains poorly defined. We aimed to investigate age-dependent differences in heart failure with mid-range (HFmrEF) vs. preserved (HFpEF) and reduced (HFrEF) ejection fraction. Methods and results: 42,987 patients, 23% with HFpEF, 22% with HFmrEF and 55% with HFrEF, enrolled in the Swedish heart failure registry were studied. HFpEF prevalence strongly increased, whereas that of HFrEF strongly decreased with higher age. All cardiac comorbidities and most non-cardiac comorbidities increased with aging, regardless of the HF phenotype. Notably, HFmrEF resembled HFrEF for ischemic heart disease prevalence in all age groups, whereas regarding hypertension it was more similar to HFpEF in age ≥ 80 years, to HFrEF in age < 65 years and intermediate in age 65–80 years. All-cause mortality risk was higher in HFrEF vs. HFmrEF for all age categories, whereas HFmrEF vs. HFpEF reported similar risk in ≥ 80 years old patients and lower risk in < 65 and 65–80 years old patients. Predictors of mortality were more likely cardiac comorbidities in HFrEF but more likely non-cardiac comorbidities in HFpEF and HFmrEF with < 65 years. Differences among HF phenotypes for comorbidities were less pronounced in the other age categories. Conclusion: HFmrEF appeared as an intermediate phenotype between HFpEF and HFrEF, but for some characteristics such as ischemic heart disease more similar to HFrEF. With aging, HFmrEF resembled more HFpEF. Prognosis was similar in HFmrEF vs. HFpEF and better than in HFrEF. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.
  • Fu, Michael, 1963, et al. (författare)
  • Implementation of sacubitril/valsartan in Sweden: clinical characteristics, titration patterns, and determinants
  • 2020
  • Ingår i: Esc Heart Failure. - : WILEY PERIODICALS, INC. - 2055-5822.
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims The aim of this study is to study the introduction of sacubitril/valsartan (sac/val) in Sweden with regards to regional differences, clinical characteristics, titration patterns, and determinants of use and discontinuation. Methods and results A national cohort of heart failure was defined from the Swedish Prescribed Drug Register and National Patient Register. A subcohort with additional data from the Swedish Heart Failure Registry (SwedeHF) was also studied. Cohorts were subdivided as per sac/val prescription and registration in SwedeHF. Median sac/val prescription rate was 20 per 100 000 inhabitants. Between April 2016 and December 2017, we identified 2037 patients with >= 1 sac/val prescription, of which 1144 (56%) were registered in SwedeHF. Overall, patients prescribed with sac/val were younger, more frequently male, and had less prior cardiovascular disease than non-sac/val patients. In SwedeHF subcohort, patients prescribed with sac/val had lower ejection fraction. Overall, younger age [hazard ratio 2.81 (95% confidence interval 2.45-3.22)], registration in SwedeHF [1.97 (1.83-2.12)], male gender [1.50 (1.37-1.64)], ischaemic heart disease [1.50 (1.39-1.62)], lower left ventricular ejection fraction [3.06 (2.18-4.31)], and New York Heart Association IV [1.50 (1.22-1.84)] were predictors for sac/val use. As initiation dose in the sac/val cohort, 38% received 24/26 mg, 54% 49/51 mg, and 9% 97/103 mg. Up-titration to the target dose was achieved in 57% of the overall cohort over a median follow-up of 6 months. The estimated treatment persistence for any dose at 360 days was 82%. Conclusions Implementation of sac/val in Sweden was slow and varied five-fold across different regions; younger age, male, SwedeHF registration, and ischaemic heart disease were among the independent predictors of receiving sac/val. Overall, treatment persistence and tolerability was high.
  • Gijsberts, Crystel M., et al. (författare)
  • Ethnic differences in the association of QRS duration with ejection fraction and outcome in heart failure
  • 2016
  • Ingår i: Heart. - : BMJ PUBLISHING GROUP. - 1355-6037 .- 1468-201X. ; 102:18, s. 1464-1471
  • Tidskriftsartikel (refereegranskat)abstract
    • Background QRS duration (QRSd) criteria for device therapy in heart failure (HF) were derived from predominantly white populations and ethnic differences are poorly understood. Methods We compared the association of QRSd with ejection fraction (EF) and outcomes between 839 Singaporean Asian and 11221 Swedish white patients with HF having preserved EF (HFPEF)and HF having reduced EF (HFREF) were followed in prospective population-based HF studies. Results Compared with whites, Asian patients with HF were younger (62 vs 74years, pamp;lt;0.001), had smaller body size (height 163 vs 171cm, weight 70 vs 80kg, both pamp;lt;0.001) and had more severely impaired EF (EF was amp;lt;30% in 47% of Asians vs 28% of whites). Overall, unadjusted QRSd was shorter in Asians than whites (101 vs 104ms, pamp;lt;0.001). Lower EF was associated with longer QRSd (pamp;lt;0.001), with a steeper association among Asians than whites (p(interaction)amp;lt;0.001), independent of age, sex and clinical covariates (including body size). Excluding patients with left bundle branch block (LBBB) and adjusting for clinical covariates, QRSd was similar in Asians and whites with HFPEF, but longer in Asians compared with whites with HFREF (p=0.001). Longer QRSd was associated with increased risk of HF hospitalisation or death (absolute 2-year event rate for 120ms was 40% and for amp;gt;120ms it was 52%; HR for 10ms increase of QRSd was 1.04 (1.03 to 1.06), pamp;lt;0.001), with no interaction by ethnicity. Conclusion We found ethnic differences in the association between EF and QRSd among patients with HF. QRS prolongation was similarly associated with increased risk, but the implications for ethnicity-specific QRSd cut-offs in clinical decision-making require further study.
  • Karason, Kristjan, 1962, et al. (författare)
  • Randomized trial of a left ventricular assist device as destination therapy versus guideline-directed medical therapy in patients with advanced heart failure. Rationale and design of the SWEdish evaluation of left Ventricular Assist Device (SweVAD) trial
  • 2020
  • Ingår i: European Journal of Heart Failure. - : WILEY. - 1388-9842 .- 1879-0844. ; 22:4, s. 739-750
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims Patients with advanced heart failure (AdHF) who are ineligible for heart transplantation (HTx) can become candidates for treatment with a left ventricular assist device (LVAD) in some countries, but not others. This reflects the lack of a systematic analysis of the usefulness of LVAD systems in this context, and of their benefits, limitations and cost-effectiveness. The SWEdish evaluation of left Ventricular Assist Device (SweVAD) study is a Phase IV, prospective, 1:1 randomized, non-blinded, multicentre trial that will examine the impact of assignment to mechanical circulatory support with guideline-directed LVAD destination therapy (GD-LVAD-DT) using the HeartMate 3 (HM3) continuous flow pump vs. guideline-directed medical therapy (GDMT) on survival in a population of AdHF patients ineligible for HTx. Methods A total of 80 patients will be recruited to SweVAD at the seven university hospitals in Sweden. The study population will comprise patients with AdHF (New York Heart Association class IIIB-IV, INTERMACS profile 2-6) who display signs of poor prognosis despite GDMT and who are not considered eligible for HTx. Participants will be followed for 2 years or until death occurs. Other endpoints will be determined by blinded adjudication. Patients who remain on study-assigned interventions beyond 2 years will be asked to continue follow-up for outcomes and adverse events for up to 5 years. Conclusion The SweVAD study will compare survival, medium-term benefits, costs and potential hazards between GD-LVAD-DT and GDMT and will provide a valuable reference point to guide destination therapy strategies for patients with AdHF ineligible for HTx.
  • Lund, Lars H, et al. (författare)
  • Association between enrolment in a heart failure quality registry and subsequent mortality-a nationwide cohort study.
  • 2017
  • Ingår i: European Journal of Heart Failure. - : John Wiley & Sons. - 1388-9842 .- 1879-0844.
  • Tidskriftsartikel (refereegranskat)abstract
    • AIMS: Heart failure (HF) quality registries report quality of care but it is unknown whether they improve outcomes. The aims were to assess predictors of enrolment in a HF registry, test the hypothesis that enrolment in a HF registry is associated with reduced mortality, and assess potential explanatory factors for this reduction in mortality, if present.METHODS AND RESULTS: We conducted a nationwide prospective cohort study of patients with new-onset HF registered in the Swedish National Patient Registry (NPR, a mandatory registry of ICD-code diagnoses) with or without concurrent registration in the Swedish Heart Failure Registry (SwedeHF, a voluntary quality reporting registry) 2006-2013. The association between demographics, co-morbidities and medications, and enrolment in the SwedeHF, was assessed using multivariable logistic regression. The association between enrolment in the SwedeHF and all-cause mortality was assessed using multivariable Cox regression, with adjustment for demographics, co-morbidities and medications. A total of 231 437 patients were included, of which 21 888 (9.5%) were in the SwedeHF [age (mean ± standard deviation) 74 ± 13 years; 41% women; 68% inpatients] and 209 549 (90.5%) were not (age 78 ± 12 years, 50% women; 79% inpatients). Selected variables independently associated with enrolment in the SwedeHF were male sex, younger age, higher education, absent co-morbidities and co-morbidity-related medications, and use of HF and cardiovascular medications. Over a median (interquartile range) follow-up of 874 (247-1667) days, there were 13.0 vs. 20.8 deaths per 100 patient-years (P < 0.001). The hazard ratio (95% confidence interval) for death for the SwedeHF yes vs. no was 0.65 (0.63-0.66) crude, and increased to 0.80 (0.78-0.81) after adding demographics, to 0.82 (0.80-0.84) after adding co-morbidities and co-morbidity-related medications, to 0.95 (0.93-0.97) after adding cardiovascular medications, and to 1.04 (1.02-1.07) after adding HF-specific medications.CONCLUSION: Heart failure patients of male sex, younger age, and higher education were more likely to be enrolled in a HF quality registry. Enrolment was associated with reduced all-cause mortality that was explained by demographic differences and better utilization of cardiovascular and HF medications.
  • Lund, Lars H, et al. (författare)
  • Effect of expanding evidence and evolving clinical guidelines on the prevalence of indication for cardiac resynchronization therapy in patients with heart failure
  • 2018
  • Ingår i: European Journal of Heart Failure. - : John Wiley & Sons. - 1388-9842 .- 1879-0844. ; 20:4, s. 769-777
  • Tidskriftsartikel (refereegranskat)abstract
    • AIMS: To assess the prevalence of indication for cardiac resynchronization therapy (CRT) in patients with heart failure (HF) and reduced ejection fraction (EF) when recommendations from evolving European Society of Cardiology (ESC) guidelines are considered.METHODS AND RESULTS: Unique patients (n=17 193) with EF ≤39% and key data available for evaluation of CRT indication from the Swedish HF Registry were included. Indication for CRT was defined as either CRT implanted or CRT device absent but fulfilling criteria for class I-IIa recommendations in ESC guidelines published between 2005/2007 and 2016. Prevalence was calculated as the ratio of patients with CRT indication to the study population. The prevalence of CRT indication increased from 24.5% when the 2005/2007 ESC guidelines were considered to a peak of 30.0% when the 2013 ESC guidelines were considered (P<0.001, 22.4% relative increase). Compared to the 2013 ESC guidelines, the prevalence declined significantly when the 2016 ESC guidelines were used as determinant for CRT indication (26.8%, 10.7% relative reduction, P<0.001). Actual CRT utilization was 6.8%.CONCLUSION: Among patients with HF and reduced EF, the prevalence of CRT indication increased significantly comparing recommendations from ESC guidelines published between 2005/2007 and 2013, but then declined when the 2016 ESC guidelines were considered. The 2005-2013 increase may reflect the expansion of documented CRT efficacy to New York Heart Association class II, whereas the subsequent drop likely results from the more stringent criteria for QRS duration in the 2016 ESC guidelines. Actual CRT utilization is lower than indicated, regardless of which guidelines are considered.
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