Door de bomen het bos zien

SOLVA beoogt met het syntheseonderzoek Door de bomen het bos zien. Een landschapsreconstructie van een microregio in de Zuid-Vlaamse leemstreek tussen de late ijzertijd en het begin van de late middeleeuwen een eerste proeve tot microregionaal landschapsonderzoek te realiseren, gekaderd binnen een archeologische context, aan de hand van het synthetiseren van paleo-ecologische informatie en een confrontatie met de archeologische bronnen. Meer specifiek zal de nadruk hierbij liggen op palynologisch en macrobotanisch onderzoek, waar mogelijk aangevuld met anthracologisch onderzoek. Als onderzoeksgebied is geopteerd voor de Scheldevallei en de aan weerszijden flankerende heuvelzones in de Zuid-Vlaamse leemstreek, op de grens van de provincies Oost- en West-Vlaanderen. De belangrijkste doelstelling van dit project is het onderzoeken van de landschapsontwikkeling in de Scheldevallei in de Zuid-Vlaamse leemstreek in relatie tot de menselijke aanwezigheid tussen de late ijzertijd en het begin van de late middeleeuwen

Skin lesions suspected of malignancy:an increasing burden on general practice

BACKGROUND: Skin cancer is believed to impose a heavy burden on healthcare services, but the burden of skin lesions suspected of malignancy on primary healthcare has never been evaluated. Therefore the aim of this study was to determine the demand for care in general practice due to these suspected skin lesions (i.e. lesions that are suspected of malignancy by either the patient or the GP). METHODS: Registry study based on data (2001–2010) from the Registration Network Groningen. This is a general practice registration network in the northern part of the Netherlands with an average annual population of approximately 30,000 patients. All patient contacts are coded according to the International Classification of Primary Care (ICPC). Consultations for skin lesions suspected of malignancy were selected according to the assigned ICPC codes. Subsequently, the number of consultations per year and the annual percent change in number of contacts (using the JoinPoint regression program) were calculated and analysed. Additionally, the percentage of patients referred to secondary care or receiving minor surgery within one year after the first contact were calculated. RESULTS: From 2001 onwards we found an annual increase in demand for care due to skin lesions suspected of malignancy of 7.3% (p < 0.01) and in 2010 the benign:malignant ratio was 10:1. In total 13.0% of the patients were referred and after 2006, minor surgery was performed on 31.2% of the patients. Most surgeries and referrals took place within 30 days. CONCLUSIONS: Suspected skin lesions impose an increasing burden on primary healthcare and most likely on healthcare costs as well. General practitioners should therefore be trained in diagnosing skin lesions suspected of malignancy, as a high diagnostic accuracy can save lives in the case of melanoma, and may also prevent unnecessary, costly, excisions and referrals to secondary healthcare

Cancer and heart disease:associations and relations

Emerging evidence supports that cancer incidence is increased in patients with cardiovascular (CV) disease and heart failure (HF), and patients with HF frequently die from cancer. Recently, data have been generated showing that circulating factors in relation to HF promote tumour growth and development in murine models, providing proof that a causal relationship exists between both diseases. Several common pathophysiological mechanisms linking HF to cancer exist, and include inflammation, neuro-hormonal activation, oxidative stress and a dysfunctional immune system. These shared mechanisms, in combination with risk factors, in concert may explain why patients with HF are prone to develop cancer. Investigating the new insights linking HF with cancer is rapidly becoming an exciting new field of research, and we herein review the most recent data. Besides insights in mechanisms, we call for clinical awareness, that is essential to optimize treatment strategies of patients having developed cancer with a history of HF. Finally, ongoing and future trials should strive for comprehensive phenotyping of both CV and cancer end points, to allow optimal usefulness of data, and to better describe and understand common characteristics of these two lethal diseases

Are lower urinary tract symptoms in men associated with cardiovascular diseases in a primary care population:a registry study

BACKGROUND: Although lower urinary tract symptoms (LUTS) seem to be related to cardiovascular disease (CVD) in men, it is unclear whether this relationship is unbiased. In order to investigate this relationship, we used longitudinal data for establishing the possible predictive value of LUTS for the development of CVD in a primary care population. METHODS: We performed a registry study using data from the Registration Network Groningen (RNG). All data from men aged 50 years and older during the study period from 1 January 1998 up to 31 December 2008 were collected. Cox proportional hazard regression analysis was used to determine the association between the proportions of CVD (outcome) and LUTS in our population. RESULTS: Data from 6614 men were analysed. The prevalence of LUTS increased from 92/1000 personyears (py) in 1998 up to 183/1000 py in 2008. For cardiovascular diseases the prevalence increased from 176/1000 py in 1998 up to 340/1000 py in 2008. The incidence numbers were resp. 10.2/1000 py (1998) and 5.1/1000 py (2008) for LUTS, and 12.9/1000 py (1998) and 10.4/1000 py (2008) for CVD. Of all men, 23.2% reported CVD (41.1% in men with LUTS vs 19.5% in men without LUTS, p < 0.01). The hazard ratio of LUTS for cardiovascular events, compared to no LUTS, in the adjusted multivariate model, was 0.921(95% CI: 0.824 - 1.030; p = 0.150). CONCLUSION: Based on the results, LUTS is not a factor that must be taken into account for the early detection of CVD in primary care

Left atrial volume and left ventricular mass indices in heart failure with preserved and reduced ejection fraction

Aims: Two key echocardiographic parameters that are currently used to diagnose heart failure (HF) with preserved ejection fraction (HFpEF) are left atrial volume index (LAVi) and left ventricular mass index (LVMi). We investigated whether patients' characteristics, biomarkers, and co-morbidities are associated with these parameters and whether the relationships differ between patients with HFpEF or HF with reduced ejection fraction (HFrEF). Methods: We consecutively enrolled 831 outpatients with typical signs and symptoms of HF and elevated N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels and categorized patients based upon left ventricular ejection fraction (LVEF): LVEF < 40% (HFrEF), LVEF between 40% and 50% (HF with mid-range ejection fraction), and LVEF ≥ 50% (HFpEF). The study includes consecutively enrolled HF patients from an HF outpatient clinic at a tertiary medical centre in the Netherlands. All patients underwent baseline characterization, laboratory measurements, and echocardiography. Results: Four hundred sixty-nine patients had HFrEF, 189 HF with mid-range ejection fraction, and 173 HFpEF. The patients with HFrEF were rather male [HFrEF: 323 (69%); HFpEF: 80 (46%); P < 0.001], and the age was comparable (HFrEF 67 ± 13; HFpEF 70 ± 14; P = 0.069). In HFpEF, more patients had hypertension [190 (40.5%); 114 (65.9%); P < 0.001], higher body mass indices (27 ± 8; 30 ± 7; P < 0.001), and atrial fibrillation [194 (41.4); 86 (49.7); P = 0.029]. The correlation analyses showed that in HFrEF patients, LAVi was significantly associated with age (β 0.293; P < 0.001), male gender (β 0.104; P = 0.042), body mass index (β −0160; P = 0.002), diastolic blood pressure (β −0.136; P < 0.001), New York Heart Association (β 0.174; P = 0.001), atrial fibrillation (β 0.381; P < 0.001), galectin 3 (β 0.230; P < 0.001), NT-proBNP (β 0.183; P < 0.001), estimated glomerular filtration rate (β −0.205; P < 0.001), LVEF (β −0.173; P = 0.001), and LVMi (β 0.337; P < 0.001). In HFpEF patients, only age (β 0.326; P < 0.001), atrial fibrillation (β 0.386; P < 0.001), NT-proBNP (β 0.176; P = 0.036), and LVMi (β 0.213; P = 0.013) were associated with LAVi. Conclusions: Although LVMi and LAVi are hallmark parameters to diagnose HFpEF, they only correlate with a few characteristics of HF and mainly with atrial fibrillation. In contrast, in HFrEF patients, LAVi relates strongly to several other HF parameters. These findings underscore the complexity in visualizing the pathophysiology of HFpEF and question the relation between cardiac structural remodeling and the impact of co-morbidities

A Systematic Review and Network Meta-Analysis of Pharmacological Treatment of Heart Failure With Reduced Ejection Fraction

Objectives: This study sought to estimate and compare the aggregate treatment benefit of pharmacological therapy for heart failure (HF) with reduced ejection fraction. Background: The estimated treatment effects of various combinations of contemporary HF medical therapies are not well characterized. Methods: We performed a systematic network meta-analysis, using MEDLINE/EMBASE and the Cochrane Central Register of Controlled Trials for randomized controlled trials published between January 1987 and January 2020. We included angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers (BB), mineralocorticoid receptor antagonists (MRAs), digoxin, hydralazine-isosorbide dinitrate, ivabradine, angiotensin receptor–neprilysin inhibitors (ARNi), sodium glucose cotransporter-2 inhibitors (SGLT2i), vericiguat, and omecamtiv-mecarbil. The primary outcome was all-cause death. We estimated the life-years gained in 2 HF populations (BIOSTAT-CHF [BIOlogy Study to TAilored Treatment in Chronic Heart Failure] and ASIAN-HF [Asian Sudden Cardiac Death in Heart Failure Registry]). Results: We identified 75 relevant trials representing 95,444 participants. A combination of ARNi, BB, MRA, and SGLT2i was most effective in reducing all-cause death (HR: 0.39; 95% CI: 0.31-0.49); followed by ARNi, BB, MRA, and vericiguat (HR: 0.41; 95% CI: 0.32-0.53); and ARNi, BB, and MRA (HR: 0.44; 95% CI: 0.36-0.54). Results were similar for the composite outcome of cardiovascular death or first hospitalization for HF (HR: 0.36; 95% CI: 0.29-0.46 for ARNi, BB, MRA, and SGLT2i; HR: 0.44; 95% CI: 0.35-0.56 for ARNi, BB, MRA, and omecamtiv-mecarbil; and HR: 0.43; 95% CI: 0.34-0.55 for ARNi, BB, MRA, and vericiguat). The estimated additional number of life-years gained for a 70-year-old patient on ARNi, BB, MRA, and SGLT2i was 5.0 years (2.5-7.5 years) compared with no treatment in secondary analyses. Conclusions: In patients with HF with reduced ejection fraction, the estimated aggregate benefit is greatest for a combination of ARNi, BB, MRA, and SGLT2i

The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unreponsive to standard heart failure therapy

Phospholamban (PLN) plays a role in cardiomyocyte calcium handling as primary inhibitor of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). The p.(Arg14del) pathogenic variant in the PLN gene results in a high risk of developing dilated or arrhythmogenic cardiomyopathy with heart failure. There is no established treatment other than standard heart failure therapy or heart transplantation. In this study, we generated a novel mouse model with the PLN-R14del pathogenic variant, performed detailed phenotyping, and tested the efficacy of established heart failure therapies eplerenone or metoprolol. Heterozygous PLN-R14del mice demonstrated increased susceptibility to ex vivo induced arrhythmias, and cardiomyopathy at 18 months of age, which was not accelerated by isoproterenol infusion. Homozygous PLN-R14del mice exhibited an accelerated phenotype including cardiac dilatation, contractile dysfunction, decreased ECG potentials, high susceptibility to ex vivo induced arrhythmias, myocardial fibrosis, PLN protein aggregation, and early mortality. Neither eplerenone nor metoprolol administration improved cardiac function or survival. In conclusion, our novel PLN-R14del mouse model exhibits most features of human disease. Administration of standard heart failure therapy did not rescue the phenotype, underscoring the need for better understanding of the pathophysiology of PLN-R14del-associated cardiomyopathy. This model provides a great opportunity to study the pathophysiology, and to screen for potential therapeutic treatments

Author Correction:The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unresponsive to standard heart failure therapy (Scientific Reports, (2020), 10, 1, (9819), 10.1038/s41598-020-66656-9)

The title in the original version of this Article contained a typographical error of ‘unresponsive’. The error has now been corrected in the PDF and HTML versions of the Article

Identifying Pathophysiological Mechanisms in Heart Failure With Reduced Versus Preserved Ejection Fraction

Background: Information on the pathophysiological differences between heart failure with reduced ejection fraction (HFrEF) versus heart failure with preserved ejection fraction (HFpEF) is needed Objectives: The purpose of this study was to establish biological pathways specifically related to HFrEF and HFpEF. Methods: The authors performed a network analysis to identify unique biomarker correlations in HFrEF and HFpEF using 92 biomarkers from different pathophysiological domains in a cohort of 1,544 heart failure (HF) patients. Data were independently validated in 804 patients with HF. Networks were enriched with existing knowledge on protein–protein interactions and translated into biological pathways uniquely related to HFrEF, HF with a midrange ejection fraction, and HFpEF. Results: In the index cohort (mean age 74 years; 34% female), 718 (47%) patients had HFrEF (left ventricular ejection fraction [LVEF] <40%) and 431 (27%) patients had HFpEF (LVEF ≥50%). A total of 8 (12%) correlations were unique for HFrEF and 6 (9%) were unique to HFpEF. Central proteins in HFrEF were N-terminal B-type natriuretic peptide, growth differentiation factor-15, interleukin-1 receptor type 1, and activating transcription factor 2, while central proteins in HFpEF were integrin subunit beta-2 and catenin beta-1. Biological pathways in HFrEF were related to DNA binding transcription factor activity, cellular protein metabolism, and regulation of nitric oxide biosynthesis. Unique pathways in patients with HFpEF were related to cytokine response, extracellular matrix organization, and inflammation. Biological pathways of patients with HF with a midrange ejection fraction were in between HFrEF and HFpEF. Conclusions: Network analysis showed that biomarker profiles specific for HFrEF are related to cellular proliferation and metabolism, whereas biomarker profiles specific for HFpEF are related to inflammation and extracellular matrix reorganization. (The BIOlogy Study to TAilored Treatment in Chronic Heart Failure [BIOSTAT-CHF]; EudraCT 2010-020808-29

Novel Endotypes in Heart Failure:Effects on Guideline-Directed Medical Therapy

Aims: We sought to determine subtypes of patients with heart failure (HF) with a distinct clinical profile and treatment response, using a wide range of biomarkers from various pathophysiological domains. Methods and results: We performed unsupervised cluster analysis using 92 established cardiovascular biomarkers to identify mutually exclusive subgroups (endotypes) of 1802 patients with HF and reduced ejection fraction (HFrEF) from the BIOSTAT-CHF project. We validated our findings in an independent cohort of 813 patients. Based on their biomarker profile, six endotypes were identified. Patients with endotype 1 were youngest, less symptomatic, had the lowest N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and lowest risk for all-cause mortality or hospitalization for HF. Patients with endotype 4 had more severe symptoms and signs of HF, higher NT-proBNP levels and were at highest risk for all-cause mortality or hospitalization for HF [hazard ratio (HR) 1.4; 95% confidence interval (CI) 1.1–1.8]. Patients with endotypes 2, 3, and 5 were better uptitrated to target doses of beta-blockers (P &lt; 0.02 for all). In contrast to other endotypes, patients with endotype 5 derived no potential survival benefit from uptitration of angiotensin-converting enzyme-inhibitor/angiotensin-II receptor blocker and beta-blockers (Pinteraction &lt;0.001). Patients with endotype 2 (HR 1.29; 95% CI 1.10–1.42) experienced possible harm from uptitration of beta-blockers in contrast to patients with endotype 4 and 6 that experienced benefit (Pinteraction for all &lt;0.001). Results were strikingly similar in the independent validation cohort. Conclusion: Using unsupervised cluster analysis, solely based on biomarker profiles, six distinct endotypes were identified with remarkable differences in characteristics, clinical outcome, and response to uptitration of guideline directed medical therapy