End-stage heart failure and left ventricular mechanical support : clinical and fundamental aspects

This thesis deals about mechanical support in en-stage heart failure. The introduction provides an overview of some clinical aspects of heart failure and the pathofysiology, focussing on remodeling. Chapter 2 reports the results of 38 patients undergoing implantation of a left ventricular assist device (LVAD) as a bridge to heart transplantation. 87 % survived the first postoperative month, and 76 % of the patients were successfully transplanted after a mean duration of support of 206±129 days. In chapter 3 exercise performance of patients supported by a LVAD is reported. Twelve weeks after LVAD implantation peak VO2 is comparable to that at 12 weeks and one year after heart transplantation (peak VO2: 22.8±5.3, 24.6±3.3 and 26.2±3.8 ml/kg/min, respectively). Therefore, with regard to exercise capacity an LVAD is fully compatible with activities of normal daily life. Chapter 4 describes the histologic features of cardiomyocytes, with emphasis on the contractile proteins. At the time of LVAD implantation widespread distortion of the staining pattern of the thin contractile proteins and titin was seen. In contrast, myosin staining pattern was preserved. After LVAD support, during a period of 213±135 days, the thin contractile proteins and titin showed improvement, but no normalization. Cardiomyocyte cross-sectional area decreased 36% after LVAD support, but also did not normalize. The persistence of severe structural myocyte damage in this study group does not support complete recovery of myocyte histologic features after a period of unloading of the heart by LVAD support. Chapter 5 focuses on cardiomyocyte cell death in patients with end-stage heart failure, before and after LVAD support. Before LVAD support apoptosis incidence was low (0.8% of cardiomyocytes), further decreasing after support (0.1% of cardiomyocytes). The apoptosis inducing mediators and their receptors were all present before and after LVAD support. The apoptosis inhibitory protein FLIP was widely expressed in cardiomyocytes before and after LVAD support, with m-RNA levels comparable to that in normal controls. This may suggest that FLIP is an important factor in the prevention of cardiomyocyte apoptosis. Chapter 6 reports the comparison of the morphology of the contractile proteins in biopsies of the left- and right ventricle and the interventricular septum to investigate if right ventricular biopsies might be used to monitor reverse remodeling in the left ventricle. The staining pattern of all these biopsies was identical. Furthermore, small biopsies taken with a diagnostic bioptome were representative for the histologic findings of the myofilaments in larger biopsies. With regard to the morphology of the contractile proteins, prospective biopsies of the right ventricle may be a way of monitoring reverse remodeling of the left ventricle during LVAD support. Chapter 7 is a general discussion of the results of the investigations included in this thesis. Probably, mechanical circulatory support can be used in the near future as an alternative to heart transplantation. The use of mechanical support as a bridge to recovery of cardiac function in end-stage heart failure is presently highly experimental and unpredictable

Understanding Outstanding: quality assurance in colonoscopy

Since a couple of years, quality assurance (QA) stands at the core of the attention in the healthcare sector. Especially after the publication in 2000 of the Institute of Medicine’s report ‘To err is human’ the interest in QA has taken a quantum leap and many quality initiatives have been developed. This report revealed that every year in the United States approximately 98,000 patients died because of medical errors. Following this report, within the healthcare sector the awareness arose that the quality of the service had to improve, with special attention to safety and patient experiences. Since then the healthcare sector has learned some important lessons in QA from other industries such as the airline industry and energy sector, which are generally classified as ultra-safe organizations. Gastrointestinal endoscopy has been one of the medicine specialties which enrolled important quality initiatives. Especially since the introduction of colorectal cancer (CRC) screening programs, many efforts have been undertaken to better understand the concept of high quality endoscopy. CRC screening has been proven to decrease the incidence of CRC, and CRC related mortality. Therefore many institutions and societies recommend to screen asymptomatic individuals by fecal occult blood tests, flexible sigmoidoscopy, or colonoscopy. As these screening programs involve healthy individuals, the cost-effectiveness of such programmatic screening approaches is highly dependent on the quality of the procedure, but also on pre- and post-procedure quality aspects to improve screenee experiences and thereby the uptake of and adherence to screening modalities. In the Netherlands, CRC screening is about to start in 2013 by means of biennial fecal immunochemical testing. To attain the highest effect a comprehensive QA program should be enrolled with major focus on endoscopy as secondary screening method, as is recommended now by the European Union. The other diagnostic and therapeutic service

Patient-reported outcomes in left ventricular assist device therapy:a systematic review and recommendations for clinical research and practice

Background-Technological advancements of left ventricular assist devices (LVAD) have created today's potential for extending the lives of patients with end-stage heart failure. Few studies have examined the effect of LVAD therapy on patient-reported outcomes (PROs), such as health status, quality of life, and anxiety/depression, despite poor PROs predicting mortality and rehospitalization in patients with heart failure. In this systematic review, we provide an overview of available evidence on the impact of LVAD therapy on PROs and discuss recommendations for clinical research and practice. Methods and Results-A systematic literature search identified 16 quantitative studies with a sample size >= 10 (mean +/- SD age=50.1 +/- 12.6 years) that examined the impact of LVAD therapy on PROs using a quantitative approach. Initial evidence suggests an improvement in health status, anxiety, and depression in the first few months after LVAD implantation. However, PRO scores of patients receiving LVAD therapy are still lower for physical, social, and emotional functioning compared with transplant recipients. These studies had several methodological shortcomings, including the use of relatively small sample sizes, and only a paucity of studies focused on anxiety and depression. Conclusions-There is a paucity of studies on the patient perspective of LVAD therapy. To advance the field of LVAD research and to optimize the care of an increasingly growing population of patients receiving LVAD therapy, more well-designed large-scale studies are needed to further elucidate the impact of LVAD therapy on PROs. (Circ Heart Fail. 2011;4:714-723.

Automatic Identification of Patients With Unexplained Left Ventricular Hypertrophy in Electronic Health Record Data to Improve Targeted Treatment and Family Screening

Background: Unexplained Left Ventricular Hypertrophy (ULVH) may be caused by genetic and non-genetic etiologies (e.g., sarcomere variants, cardiac amyloid, or Anderson-Fabry's disease). Identification of ULVH patients allows for early targeted treatment and family screening. Aim: To automatically identify patients with ULVH in electronic health record (EHR) data using two computer methods: text-mining and machine learning (ML). Methods: Adults with echocardiographic measurement of interventricular septum thickness (IVSt) were included. A text-mining algorithm was developed to identify patients with ULVH. An ML algorithm including a variety of clinical, ECG and echocardiographic data was trained and tested in an 80/20% split. Clinical diagnosis of ULVH was considered the gold standard. Misclassifications were reviewed by an experienced cardiologist. Sensitivity, specificity, positive, and negative likelihood ratios (LHR+ and LHR-) of both text-mining and ML were reported. Results: In total, 26,954 subjects (median age 61 years, 55% male) were included. ULVH was diagnosed in 204/26,954 (0.8%) patients, of which 56 had amyloidosis and two Anderson-Fabry Disease. Text-mining flagged 8,192 patients with possible ULVH, of whom 159 were true positives (sensitivity, specificity, LHR+, and LHR- of 0.78, 0.67, 2.36, and 0.33). Machine learning resulted in a sensitivity, specificity, LHR+, and LHR- of 0.32, 0.99, 32, and 0.68, respectively. Pivotal variables included IVSt, systolic blood pressure, and age. Conclusions: Automatic identification of patients with ULVH is possible with both Text-mining and ML. Text-mining may be a comprehensive scaffold but can be less specific than machine learning. Deployment of either method depends on existing infrastructures and clinical applications

Prognostic biomarker soluble ST2 exhibits diurnal variation in chronic heart failure patients

Aim: Soluble suppression of tumorigenicity-2 (sST2) is a strong prognostic biomarker in heart failure. The emerging understanding of circadian biology in cardiovascular disease may lead to novel applications in prognosis and diagnosis and may provide insight into mechanistic aspects of the disease–biomarker interaction. So far, it is unknown whether sST2 exhibits a diurnal rhythm. Repeated measurements of sST2 may aid in clinical decision making. The goal of this study was to investigate whether sST2 exhibits diurnal variation in patients with heart failure with reduced ejection fraction (HFrEF) and in control subjects, thereby enhancing its diagnostic and prognostic values. Methods and results: The study comprised 32 subjects: 16 HFrEF patients and 16 controls. Blood was collected at seven subsequent time points during a 24 h time period. sST2, N-terminal pro-B-type natriuretic peptide (NT-proBNP), melatonin, and cortisol were measured from serum. Peak values of sST2 clustered at daytime (modal value: 5 p.m.) in 87.6% of all subjects (81.3% of patients, P = 0.021; 93.8% of controls, P = 0.001), and minimum concentrations at night-time (modal value: 5 a.m.) in 84.4% (87.5% of patients, P = 0.004 81.3% of controls, P = 0.021). A cosinor analysis of mean normalized sST2 values revealed significant cosine shaped 24 h oscillations of patients (P = 0.026) and controls (P = 0.037). NT-proBNP in contrast did not show a diurnal rhythm, while melatonin and cortisol patterns were intact in all subjects. Conclusions: sST2 exhibits a diurnal rhythm with lower values in the morning than in the late afternoon. This new insight could lead to refinement of its diagnostic and prognostic values through specified and consistent sampling times with repeated measurements. For example, by measuring sST2 during the afternoon, when levels are at their highest, false negatives on prognosis prediction could be avoided

High Resolution Systematic Digital Histological Quantification of Cardiac Fibrosis and Adipose Tissue in Phospholamban p.Arg14del Mutation Associated Cardiomyopathy

Myocardial fibrosis can lead to heart failure and act as a substrate for cardiac arrhythmias. In dilated cardiomyopathy diffuse interstitial reactive fibrosis can be observed, whereas arrhythmogenic cardiomyopathy is characterized by fibrofatty replacement in predominantly the right ventricle. The p.Arg14del mutation in the phospholamban (PLN) gene has been associated with dilated cardiomyopathy and recently also with arrhythmogenic cardiomyopathy. Aim of the present study is to determine the exact pattern of fibrosis and fatty replacement in PLN p.Arg14del mutation positive patients, with a novel method for high resolution systematic digital histological quantification of fibrosis and fatty tissue in cardiac tissue. Transversal mid-ventricular slices (n = 8) from whole hearts were collected from patients with the PLN p.Arg14del mutation (age 48±16 years; 4 (50%) male). An in-house developed open source MATLAB script was used for digital analysis of Masson's trichrome stained slides (http://sourceforge.net/projects/fibroquant/). Slides were divided into trabecular, inner and outer compact myocardium. Per region the percentage of connective tissue, cardiomyocytes and fatty tissue was quantified. In PLN p.Arg14del mutation associated cardiomyopathy, myocardial fibrosis is predominantly present in the left posterolateral wall and to a lesser extent in the right ventricular wall, whereas fatty changes are more pronounced in the right ventricular wall. No difference in distribution pattern of fibrosis and adipocytes was observed between patients with a clinical predominantly dilated and arrhythmogenic cardiomyopathy phenotype. In the future, this novel method for quantifying fibrosis and fatty tissue can be used to assess cardiac fibrosis and fatty tissue in animal models and a broad range of human cardiomyopathies

Mislocalization of XPF-ERCC1 Nuclease Contributes to Reduced DNA Repair in XP-F Patients

Xeroderma pigmentosum (XP) is caused by defects in the nucleotide excision repair (NER) pathway. NER removes helix-distorting DNA lesions, such as UV–induced photodimers, from the genome. Patients suffering from XP exhibit exquisite sun sensitivity, high incidence of skin cancer, and in some cases neurodegeneration. The severity of XP varies tremendously depending upon which NER gene is mutated and how severely the mutation affects DNA repair capacity. XPF-ERCC1 is a structure-specific endonuclease essential for incising the damaged strand of DNA in NER. Missense mutations in XPF can result not only in XP, but also XPF-ERCC1 (XFE) progeroid syndrome, a disease of accelerated aging. In an attempt to determine how mutations in XPF can lead to such diverse symptoms, the effects of a progeria-causing mutation (XPFR153P) were compared to an XP–causing mutation (XPFR799W) in vitro and in vivo. Recombinant XPF harboring either mutation was purified in a complex with ERCC1 and tested for its ability to incise a stem-loop structure in vitro. Both mutant complexes nicked the substrate indicating that neither mutation obviates catalytic activity of the nuclease. Surprisingly, differential immunostaining and fractionation of cells from an XFE progeroid patient revealed that XPF-ERCC1 is abundant in the cytoplasm. This was confirmed by fluorescent detection of XPFR153P-YFP expressed in Xpf mutant cells. In addition, microinjection of XPFR153P-ERCC1 into the nucleus of XPF–deficient human cells restored nucleotide excision repair of UV–induced DNA damage. Intriguingly, in all XPF mutant cell lines examined, XPF-ERCC1 was detected in the cytoplasm of a fraction of cells. This demonstrates that at least part of the DNA repair defect and symptoms associated with mutations in XPF are due to mislocalization of XPF-ERCC1 into the cytoplasm of cells, likely due to protein misfolding. Analysis of these patient cells therefore reveals a novel mechanism to potentially regulate a cell's capacity for DNA repair: by manipulating nuclear localization of XPF-ERCC1

2019 EACTS Expert Consensus on long-term mechanical circulatory support

Long-term mechanical circulatory support (LT-MCS) is an important treatment modality for patients with severe heart failure. Different devices are available, and many-sometimes contradictory-observations regarding patient selection, surgical techniques, perioperative management and follow-up have been published. With the growing expertise in this field, the European Association for Cardio-Thoracic Surgery (EACTS) recognized a need for a structured multidisciplinary consensus about the approach to patients with LT-MCS. However, the evidence published so far is insufficient to allow for generation of meaningful guidelines complying with EACTS requirements. Instead, the EACTS presents an expert opinion in the LT-MCS field. This expert opinion addresses patient evaluation and preoperative optimization as well as management of cardiac and non-cardiac comorbidities. Further, extensive operative implantation techniques are summarized and evaluated by leading experts, depending on both patient characteristics and device selection. The faculty recognized that postoperative management is multidisciplinary and includes aspects of intensive care unit stay, rehabilitation, ambulatory care, myocardial recovery and end-of-life care and mirrored this fact in this paper. Additionally, the opinions of experts on diagnosis and management of adverse events including bleeding, cerebrovascular accidents and device malfunction are presented. In this expert consensus, the evidence for the complete management from patient selection to end-of-life care is carefully reviewed with the aim of guiding clinicians in optimizing management of patients considered for or supported by an LT-MCS device

Systematic Genetic Nomenclature for Type VII Secretion Systems

CITATION: Bitter, W., et al. 2009. Systematic genetic nomenclature for type VII secretion systems. PLoS Pathogens, 5(10): 1-6, doi: 10.1371/journal.ppat.1000507.The original publication is available at http://journals.plos.org/plospathogensMycobacteria, such as the etiological agent of human tuberculosis, Mycobacterium tuberculosis, are protected by an impermeable cell envelope composed of an inner cytoplasmic membrane, a peptidoglycan layer, an arabinogalactan layer, and an outer membrane. This second membrane consists of covalently linked, tightly packed long-chain mycolic acids [1,2] and noncovalently bound shorter lipids involved in pathogenicity [3–5]. To ensure protein transport across this complex cell envelope, mycobacteria use various secretion pathways, such as the SecA1-mediated general secretory pathway [6,7], an alternative SecA2-operated pathway [8], a twin-arginine translocation system [9,10], and a specialized secretion pathway variously named ESAT-6-, SNM-, ESX-, or type VII secretion [11–16]. The latter pathway, hereafter referred to as type VII secretion (T7S), has recently become a large and competitive research topic that is closely linked to studies of host–pathogen interactions of M. tuberculosis [17] and other pathogenic mycobacteria [16]. Molecular details are just beginning to be revealed [18–22] showing that T7S systems are complex machineries with multiple components and multiple substrates. Despite their biological importance, there has been a lack of a clear naming policy for the components and substrates of these systems. As there are multiple paralogous T7S systems within the Mycobacteria and orthologous systems in related bacteria, we are concerned that, without a unified nomenclature system, a multitude of redundant and obscure gene names will be used that will inevitably lead to confusion and hinder future progress. In this opinion piece we will therefore propose and introduce a systematic nomenclature with guidelines for name selection of new components that will greatly facilitate communication and understanding in this rapidly developing field of research.http://journals.plos.org/plospathogens/article?id=10.1371%2Fjournal.ppat.1000507Publisher's versio