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

Endomyocardial biopsy with co-localization of a lymphoplasmacytic lymphoma and AL amyloidosis

In about 4% of cases, amyloid light chain (AL) amyloidosis is due to an underlying lymphoplasmacytic lymphoma (LPL) or other monoclonal protein forming low-grade B-cell lymphoma, instead of a plasma cell neoplasm. We report an unusual case of a 55-year-old male with co-localization of an IgG positive LPL and AL amyloidosis in his endomyocardial biopsy (EMB). The patient was diagnosed 4 years earlier with a low grade B-cell non Hodgkin lymphoma stage IV, at the time classified as marginal zone lymphoma. He received several lines of treatment for his lymphoma, which had shown progressive disease. Four years after initial diagnosis, he developed increasing dyspnea on exertion. Echocardiography demonstrated left and right ventricular hypertrophy with classical apical sparing, suspicious for cardiac amyloidosis. Bone marrow biopsy revealed massive infiltration by his low grade B-cell lymphoma, which was now reclassified as LPL based on the demonstration of a MYD88 L265P mutation. An EMB confirmed the presence of amyloid, which was typed as AL amyloidosis by the use of immunoelectron microscopy. In addition, mild B-cell infiltrates were present in the EMB, which were shown to be part of his LPL by the demonstration of the MYD88 L265P mutation using the highly sensitive droplet digital polymerase chain reaction technique. This is a rare case of cardiac AL amyloidosis based on an IgG kappa positive LPL, in which not only the amyloid but also the lymphoma itself were present in the EMB. In addition, this case nicely illustrates the use of 2 highly sensitive techniques (immunoelectron microscopy and droplet digital polymerase chain reaction), which both can be performed on small, formalin-fixed paraffin-embedded biopsies

Incidence and risk factors of late right heart failure in chronic mechanical circulatory support

Background: Late right heart failure (LRHF) is a common complication during long-term left ventricular assist device (LVAD) support. We aimed to identify risk factors for LRHF after LVAD implantation. Methods: Patients undergoing primary LVAD implantation between 2006 and 2019 and surviving the perioperative period were included for this study (n = 261). Univariate Cox proportional hazards analysis was used to assess the association of clinical covariates and LRHF, stratified for device type. Variables with p < 0.10 entered the multivariable model. In a subset of patients with complete echocardiography or right catheterization data, this multivariable model was extended. Postoperative cardiopulmonary exercise test data were compared in patients with and without LRHF. Results: Nineteen percentage of patients suffered from LRHF after a median of 12 months, of which 67% required hospitalization. A history of atrial fibrillation (AF) (HR: 2.06 [1.08–3.93], p = 0.029), a higher preoperative body mass index (BMI) (HR: 1.07 [1.01–1.13], p = 0.023), and intensive care unit (ICU) duration (HR: 1.03 [1.00–1.06], p = 0.025) were independent predictors of LHRF in the multivariable model. A significant relation between the severity of tricuspid regurgitation (TR) and LRHF (HR: 1.91 [1.13–3.21], p = 0.016) was found in patients with echocardiographic data. Patients with LRHF demonstrated a lower maximal workload and peak VO2 at 6 months postoperatively. Conclusion: A history of AF, BMI, and longer ICU stay may help identify patients at high risk for LRHF. Severity of TR was significantly related to LRHF in a subset of patients

Incidence and risk factors of late right heart failure in chronic mechanical circulatory support

Background: Late right heart failure (LRHF) is a common complication during long-term left ventricular assist device (LVAD) support. We aimed to identify risk factors for LRHF after LVAD implantation. Methods: Patients undergoing primary LVAD implantation between 2006 and 2019 and surviving the perioperative period were included for this study (n = 261). Univariate Cox proportional hazards analysis was used to assess the association of clinical covariates and LRHF, stratified for device type. Variables with p < 0.10 entered the multivariable model. In a subset of patients with complete echocardiography or right catheterization data, this multivariable model was extended. Postoperative cardiopulmonary exercise test data were compared in patients with and without LRHF. Results: Nineteen percentage of patients suffered from LRHF after a median of 12 months, of which 67% required hospitalization. A history of atrial fibrillation (AF) (HR: 2.06 [1.08–3.93], p = 0.029), a higher preoperative body mass index (BMI) (HR: 1.07 [1.01–1.13], p = 0.023), and intensive care unit (ICU) duration (HR: 1.03 [1.00–1.06], p = 0.025) were independent predictors of LHRF in the multivariable model. A significant relation between the severity of tricuspid regurgitation (TR) and LRHF (HR: 1.91 [1.13–3.21], p = 0.016) was found in patients with echocardiographic data. Patients with LRHF demonstrated a lower maximal workload and peak VO2 at 6 months postoperatively. Conclusion: A history of AF, BMI, and longer ICU stay may help identify patients at high risk for LRHF. Severity of TR was significantly related to LRHF in a subset of patients

Soluble Suppression of Tumorigenicity-2 Predicts Mortality and Right Heart Failure in Patients With a Left Ventricular Assist Device

BACKGROUND: Soluble suppression of tumorigenicity-2 (sST2) predicts mortality in patients with heart failure. The predictive value of sST2 in patients with a left ventricular assist device remains unknown. Therefore, we studied the relationship between sST2 and outcome after left ventricular assist device implantation. METHODS AND RESULTS: sST2 levels of patients with a left ventricular assist device implanted between January 2015 and December 2022 were included in this observational study. The median follow-up was 25 months, during which 1573 postoperative sST2 levels were measured in 199 patients, with a median of 29 ng/mL. Survival of patients with normal and elevated preoperative levels was compared using Kaplan-Meier analysis, which did not differ significantly (P=0.22) between both groups. The relationship between postoperative sST2, survival, and right heart failure was evaluated using a joint model, which showed a significant relationship between the absolute sST2 level and mortality, with a hazard ratio (HR) of 1.20 (95% CI, 1.10– 1.130; P<0.01) and an HR of 1.22 (95% CI, 1.07–1.39; P=0.01) for right heart failure, both per 10-unit sST2 increase. The sST2 instantaneous change was not predictive for survival or right heart failure (P=0.99 and P=0.94, respectively). Multivariate joint model analysis showed a significant relationship between sST2 with mortality adjusted for NT-proBNP (N-terminal pro-B-type natriuretic peptide), with an HR of 1.19 (95% CI, 1.00–1.42; P=0.05), whereas the HR of right heart failure was not significant (1.22 [95% CI, 0.94–1.59]; P=0.14), both per 10-unit sST2 increase. CONCLUSIONS: Time-dependent postoperative sST2 predicts all-cause mortality after left ventricular assist device implantation after adjustment for NT-proBNP. Future research is warranted into possible target interventions and the optimal monitoring frequency