Early integrated palliative care in chronic heart failure and chronic obstructive pulmonary disease: protocol of a feasibility before-after intervention study.

BACKGROUND: Patients with chronic heart failure (CHF) and patients with chronic obstructive pulmonary disease (COPD) are amenable to integrated palliative care (PC); however, despite the recommendation by various healthcare organizations, these patients have limited access to integrated PC services. In this study, we present the protocol of a feasibility prospective study that aims to explore if an "early integrated PC" intervention can be performed in an acute setting (cardiology and pulmonology wards) and whether it will have an effect on (i) the satisfaction of care and (ii) the quality of life and the level of symptom control of CHF/COPD patients and their informal caregivers. METHODS: A before-after intervention study with three phases, (i) baseline phase where the control group receives standard care, (ii) training phase where the personnel is trained on the application of the intervention, and (iii) intervention phase where the intervention is applied, will be carried out in cardiology and pulmonology wards in the University Hospital Leuven for patients with advanced CHF/COPD and their informal caregivers. Eligible patients (both control and intervention group) and their informal caregivers will be asked to complete the Palliative Outcome Scale, the CANHELP Lite, and the Advance Care Planning Questionnaire at the inclusion moment and 3 months after hospital discharge. DISCUSSION: The present study will assess the feasibility of carrying out PC-focused studies in acute wards for CHF/COPD patients and draw lessons for the further integration of PC alongside standard treatment. Further, it will measure the quality of life and quality of care of patients and thus shed light on the care needs of this population. Finally, it will evaluate the potential efficacy of the "early integrated palliative care" by comparing against existing practices. TRIAL REGISTRATION: Current Controlled Trials ISRCTN24796028 (date of registration August 30, 2018).

Virulent Pseudorabies Virus Infection Induces a Specific and Lethal Systemic Inflammatory Response in Mice.

Pseudorabies virus (PRV) is an alphaherpesvirus that infects the peripheral nervous system (PNS). The natural host of PRV is the swine, but it can infect most mammals, including cattle, rodents, and dogs. In these nonnatural hosts, PRV always causes a severe acute and lethal neuropathy called the "mad itch," which is uncommon in swine. Thus far, the pathophysiological and immunological processes leading to the development of the neuropathic itch and the death of the animal are unclear. Using a footpad inoculation model, we established that mice inoculated with PRV-Becker (virulent strain) develop a severe pruritus in the foot and become moribund at 82 h postinoculation (hpi). We found necrosis and inflammation with a massive neutrophil infiltration only in the footpad and dorsal root ganglia (DRGs) by hematoxylin and eosin staining. PRV load was detected in the foot, PNS, and central nervous system tissues by quantitative reverse transcription-PCR. Infected mice had elevated plasma levels of proinflammatory cytokines (interleukin-6 [IL-6] and granulocyte colony-stimulating factor [G-CSF]) and chemokines (Gro-1 and monocyte chemoattractant protein 1). Significant IL-6 and G-CSF levels were detected in several tissues at 82 hpi. High plasma levels of C-reactive protein confirmed the acute inflammatory response to PRV-Becker infection. Moreover, mice inoculated with PRV-Bartha (attenuated, live vaccine strain) did not develop pruritus at 82 hpi. PRV-Bartha also replicated in the PNS, and the infection spread further in the brain than PRV-Becker. PRV-Bartha infection did not induce the specific and lethal systemic inflammatory response seen with PRV-Becker. Overall, we demonstrated the importance of inflammation in the clinical outcome of PRV infection in mice and provide new insights into the process of PRV-induced neuroinflammation.IMPORTANCE Pseudorabies virus (PRV) is an alphaherpesvirus related to human pathogens such as herpes simplex virus 1 and varicella-zoster virus (VZV). The natural host of PRV is the swine, but it can infect most mammals. In susceptible animals other than pigs, PRV infection always causes a characteristic lethal pruritus known as the "mad itch." The role of the immune response in the clinical outcome of PRV infection is still poorly understood. Here, we show that a systemic host inflammatory response is responsible for the severe pruritus and acute death of mice infected with virulent PRV-Becker but not mice infected with attenuated strain PRV-Bartha. In addition, we identified IL-6 and G-CSF as two main cytokines that play crucial roles in the regulation of this process. Our findings give new insights into neuroinflammatory diseases and strengthen further the similarities between VZV and PRV infections at the level of innate immunity.

Cancer After Heart Transplantation: A 25-year Single-center Perspective.

BACKGROUND: Cancer is a major cause of morbidity and mortality after heart transplantation. METHODS: We studied 541 heart transplant patients from a single center over a period of 25 years, with a mean follow-up of 10.7 years. We determined incidence, type, risk factors, and prognosis for cancer after heart transplantation. RESULTS: Cancer was diagnosed in 181 patients, at a mean of 7.7 years after transplantation. Cumulative incidence of cancer at 5, 10, and 20 years was 14%, 29%, and 60%, respectively. The most frequent cancers were spinocellular skin cancer (22%), basocellular skin cancer (19%), lung cancer (16%), lymphoma (11%) and prostate cancer (10%). Age at transplantation > 50 years (hazard ratio, 2.9; P < .001) and male recipient gender (hazard ratio, 1.7; P = .038) were significant risk factors for posttransplant malignancy on multivariate Cox proportional hazards analysis. Median patient survival after diagnosis of cancer was 2.9 years for patients with noncutaneous cancer, versus 13.1 years for patients with only skin cancer (P < .001).

RNA Profiling in Human and Murine Transplanted Hearts: Identification and Validation of Therapeutic Targets for Acute Cardiac and Renal Allograft Rejection.

Acute cellular rejection (ACR) is the adverse response of the recipient's immune system against the allogeneic graft. Using human surveillance endomyocardial biopsies (EMBs) manifesting ACR and murine allogeneic grafts, we profiled implicated microRNAs (miRs) and mRNAs. MiR profiling showed that miR-21, -142-3p, -142-5p, -146a, -146b, -155, -222, -223, and -494 increased during ACR in humans and mice, whereas miR-149-5p decreased. mRNA profiling revealed 70 common differentially regulated transcripts, all involved in immune signaling and immune-related diseases. Interestingly, 33 of 70 transcripts function downstream of IL-6 and its transcription factor spleen focus forming virus proviral integration oncogene (SPI1), an established target of miR-155, the most upregulated miR in human EMBs manifesting rejection. In a mouse model of cardiac transplantation, miR-155 absence and pharmacological inhibition attenuated ACR, demonstrating the causal involvement and therapeutic potential of miRs. Finally, we corroborated our miR signature in acute cellular renal allograft rejection, suggesting a nonorgan specific signature of acute rejection. We concluded that miR and mRNA profiling in human and murine ACR revealed the shared significant dysregulation of immune genes. Inflammatory miRs, for example miR-155, and transcripts, in particular those related to the IL-6 pathway, are promising therapeutic targets to prevent acute allograft rejection.

Cost of 1-year left ventricular assist device destination therapy in chronic heart failure: a comparison with heart transplantation.

OBJECTIVE: To analyse overall cost involved with destination therapy (DT) in comparison to transplantation (HTX) and bridging to transplantation. METHODS: Three groups of patients at one hospital were considered for this cost analysis: (1) patients included in the BENEMACS study starting May 2009 (n = 6); (2) all patients from May 2009 till May 2010 undergoing heart transplantation (n = 19); or (iii) undergoing Heartmate II implantation as a bridge to transplant (n = 13). Patients undergoing bridging were more sick (lower Intermacs class). DT patients were older (64±8 years). Cost was derived from actual hospital invoices, device, organ procurement and medical cost, and follow-up care during 1 year from implantation. Costs are presented in euro, by their mean values and standard deviation. RESULTS: One-year survivals were 83, 84, and 77%, respectively, for DT, HTX, and bridging. Costs for initial and re-hospitalizations were not different between groups. Costs for medical follow-up and medication were significantly higher for transplanted patients. The 1-year total cost was €85 531±19 823 for HTX, €125 108±32 399 for bridging, and €137 068±29 007 for DT. As 42% of the transplanted patients were bridged, the cost of the medical pathway HTX was €138 076±19 823. Assuming a 5-year survival and a similar yearly follow-up cost, the average cost per year is €42 153 for HTX, €53 637 for transplantation including the bridging cost, and €47 487 for DT. CONCLUSION: Direct transplantation without bridging is the most cost-efficient treatment. The cost per patient per year for DT is similar to HTX considering its bridging activity.

Quantitative dobutamine stress echocardiography for the early detection of cardiac allograft vasculopathy in heart transplant recipients.

BACKGROUND: A non-invasive method to detect the presence of cardiac allograft vasculopathy (CAV) remains an important goal in clinical cardiology. OBJECTIVE: To assess the value of quantitative dobutamine stress echocardiography (DSE) for the early detection of CAV. METHODS: 42 heart transplant recipients underwent DSE with acquisition of both conventional two-dimensional and colour tissue Doppler data. All studies were analysed conventionally and quantitatively using regional deformation parameters-that is, peak systolic longitudinal strain (in(peak sys)), strain rate (SR(peak sys)) and post-systolic strain index. Myocardial segments were classified as normal, mildly abnormal or severely abnormal based on correlative angiographic findings. RESULTS: At baseline, in(peak sys) was significantly lower in severely abnormal segments than in normal ones. However, at peak stress, in(peak sys) was able to separate three groups of segments. Receiver operating characteristic analysis showed an SR(peak sys) response of <0.5/s to identify patients with CAV with a sensitivity of 88%, specificity of 85% and a negative predictive value of 92%. CONCLUSION: Regional myocardial function is impaired in heart transplant recipients with CAV even when the disease is considered to be non-significant on conventional angiography. Systolic deformation parameters tended to detect the existence of CAV more accurately than conventional visual DSE assessment. Strain rate imaging during stress can therefore safely be used as a non-invasive screening test for detecting CAV in heart transplant recipients.

Airborne polyvinyl alcohol (PVA) and cellulose fibre levels in fibre-cement factories in seven European countries.

Because of their relatively high diameter, polyvinyl alcohol (PVA) fibres, as used in fibre-cement, are not fibres as defined by WHO (or other) regulations. Nevertheless, as with all particulate raw materials, it can be questioned if and to what extent particles with critical fibrous dimensions might be generated by the handling or machining of this material. In order to investigate any tendency of PVA fibres to release airborne particles with critical fibrous dimensions (WHO fibres), static and/or personal samples were taken in eight fibre-cement factories at locations where potential exposures to PVA fibres were expected to be the highest. The following locations were surveyed: the PVA fibre weighing station, where PVA bales are opened mechanically and the PVA fibres are dispersed and weighed in a dry state; the fibre-cement slate punching machine; the slate 'riven edge' cutting machine or sheet sawing machine, whichever was present in the respective factories. Since cellulose fibres are an important constituent of fibre-cement, the organic fibre concentrations observed at the machining operations include cellulose. At each factory a control sample was taken in open air. Sampling, sample preparation and sample analysis by scanning electron microscopy (SEM) were performed according to standard German procedures. Only very low number concentrations of organic WHO fibres, ranging from below detection limit to 0.006 f/ml, were found. These levels are lower than the typical levels of organic fibres commonly found in the normal personal environment (0.009-0.02 f/ml), stemming from the release of particles by a person's activities and from clothing and other textiles (bed sheets, blankets, pillow,.). We conclude that the handling of PVA fibres as well as the machining of PVA and cellulose fibre containing cement products in the fibre-cement factories surveyed have a low potential to release fibres with critical fibrous (WHO) dimensions.

Surface of localized pleural plaques quantitated by computed tomography scanning: no relation with cumulative asbestos exposure and no effect on lung function.

To evaluate if there is a relation between the size of asbestos plaques and the level of past exposure and pulmonary function, we measured the surface of localized pleural plaques found on high-resolution (HR) CT scan, using a computerized video display unit-imaging system, in 73 workers (mean age, 43.5 yr) who had worked from 23 to 27 yr in an asbestos-cement factory. Their estimated cumulative exposure to asbestos ranged from 16.4 to 98.7 fiber-years/ ml (mean, 26.3 fiber-years/ml). Lung function measurements included lung volumes, maximal expiratory flows, and diffusing capacity. A control group of 21 workers was examined by the same procedures. Plaques were detected by CT in 51 (70%) asbestos-exposed subjects and in none of the control subjects. The average calculated plaque surface was 47.9 +/- 61.7 cm2 (median, 22.1 cm2; range, 0 to 278.4 cm2). There was no relation between plaque surface and cumulative asbestos exposure (p = 0.24). In the 51 subjects with pleural plaques, the surface of the pleural lesions was not related to cumulative asbestos exposure, or to smoking history or time since first exposure. Neither the presence nor the extent of the plaques was correlated with lung function parameters.

Failure of medicine: evolution of an atrial septal defect to an Eisenmenger syndrome.

The atrial septal defect (ASD) is the most commonly diagnosed congenital defect in adults and has a prevalence of 7.5% of all congenital cardiac anomalies. Less invasive imaging techniques, especially transthoracic and transoesophageal echocardiography, provide more accurate diagnostics, resulting in earlier diagnosis and treatment. Despite these opportunities in high-tech countries, medicine may still fail in detecting initially correctable cardiac anomalies. We present a case of 41-year-old woman with an abnormal murmur at childhood that disappeared with time due to the development of an Eisenmenger syndrome. The importance of a complete haemodynamic evaluation in this patient is illustrated.

Transplantation osteoporosis and corticosteroid-induced osteoporosis in autoimmune diseases: experience with alfacalcidol.

The effect of alfacalcidol therapy on bone mineral density at the spine and proximal femur was evaluated in 112 transplant recipients (59 heart, 26 liver and 27 lung); 45 transplant cases served as controls (included in a randomised way in a placebo group) and in 42 rheumatoid arthritis cases. Liver and lung transplantation cases had before transplantation a lower bone density at the spine and femur compared to heart transplant cases. Heart transplant cases lost considerably more bone immediately after transplantation than liver and lung transplant recipients. A positive effect of 2 years alfacalcidol treatment (0.5-1 microgram/day) on bone loss was observed in all treated groups. Alfacalcidol was particularly effective against trabecular bone loss at the spine in rheumatoid arthritis patients and transplant recipients. There is a manifest difference in evolution between organ transplant groups and bone sites measured. Liver and lung transplant recipients respond better to therapy than cardiac recipients.

Peak oxygen uptake better predicts outcome than submaximal respiratory data in heart transplant candidates.

BACKGROUND: Many studies have focused on the prognostic power of peak oxygen uptake VO(2) in patients with chronic heart failure, but maximal exercise testing is not without risk. The purpose of the present study was, therefore, to assess the prognostic significance of the steepness of changes in ventilation and carbon dioxide output VO(2) during submaximal exercise in comparison with VO(2). METHODS AND RESULTS: The study population consisted of 284 adult heart transplant candidates who performed a graded maximal bicycle ergometer test with respiratory gas analysis. Using the respiratory data up to a gas exchange ratio of 1.0, 3 submaximal slopes were calculated in each patient. During follow-up (median, 1.33 years), 57 patients died and 149 had >/=1 cardiovascular event. When using Cox proportional hazards analysis, both peak VO(2) and submaximal respiratory slopes predicted outcome before and after accounting for age, sex, and body mass index. However, whereas the prognostic power of peak VO(2) was independent of submaximal respiratory data, the prognostic significance of the slopes was lost after controlling for peak VO(2). Stepwise regression analysis even selected peak VO(2) as an independent prognostic index among the following factors: cause of heart failure, ejection fraction, pulmonary vascular resistance, natremia, and the forced expiratory volume in 1 s. CONCLUSIONS: Respiratory data during submaximal exercise are significant predictors of outcome in patients with chronic heart failure, but their prognostic power is inferior to that of peak VO(2). However, these data may be useful when maximal exercise is contraindicated or not achievable.

Oxidized low density lipoprotein is a prognostic marker of transplant-associated coronary artery disease.

Retrospective studies identified oxidized low density lipoprotein (LDL) in the blood as a diagnostic marker of coronary artery disease (CAD). This prospective study sought to determine the prognostic value of oxidized LDL for CAD in cardiac transplant patients. Oxidized LDL was measured in 99 cardiac transplant patients with normal coronary angiograms at baseline and was measured again after a median follow-up of 2 years at the time of a second angiogram. Twenty-one patients developed angiographically detectable cardiac transplant vasculopathy (cases), and 78 individuals did not (controls). Cases had significantly higher baseline plasma levels of oxidized LDL than did controls: 1.18+/-0.70 versus 0.57+/-0.20 mg/dL (mean+/-SD, P<0.0001). The increase of oxidized LDL at the end of the follow-up was significantly higher in cases than in controls: 0. 75+/-0.73 mg/dL versus 0.14+/-0.27 mg/dL (P<0.0001). Baseline levels of oxidized LDL predicted cardiac transplant vasculopathy (chi(2)=16, P<0.0001) independent of pretransplant ischemic cardiomyopathy, time after transplantation, age, and serum levels of LDL and high density lipoprotein cholesterol. The development of transplant CAD was associated with a further increase of plasma levels of oxidized LDL (chi(2)=14, P=0.0002). Oxidized LDL is a prognostic marker of transplant CAD.

A probable primary HIV infection associated with acute non-specific myocarditis causing severe dilated cardiomyopathy.

A patient with a probable primary HIV infection and a biopsy proven non-specific myocarditis is reported. The patient developed a severe dilated cardiomyopathy and initially presented with global heartfailure and fever. The left ventricular function partially recovered. One week after discharge the patient was readmitted in a septic shock and died. Current hypotheses concerning the etiology of left ventricular dysfunction in HIV infection are discussed.

Out-patient versus in-hospital ambulatory 24-h blood pressure monitoring in heart transplant recipients.

OBJECTIVE: To study the effect of the environment--in-hospital vs. out-patient situation--on blood pressure as measured by ambulatory blood pressure monitoring (ABPM). PATIENTS AND METHODS: Twenty-four hour ABPM was performed sequentially in-hospital and again 9+/-3 days later on an out-patient basis, in 30 consecutive heart transplant recipients (27 men, median age 56 years, median time post-transplant 3 years). The same equipment was used on both occasions, without any interim change in medical treatment. RESULTS: Both systolic and diastolic blood pressure were higher in-hospital than as an out-patient: +7+/-7 and +6+/-5 mm Hg respectively for the 24-h average (P<0.001). Daytime and night-time pressures were affected similarly. Depending on the specific cut-off values used, 37 to 87% of the individual patients were hypertensive in-hospital; 31 to 73% of these had an acceptable blood pressure as an out-patient. The converse was very rare (0 to 3% of the total group). CONCLUSIONS: In heart transplant patients blood pressure as assessed from 24-h ABPM is lower in the home environment than during a hospital stay. The post-transplant attenuation of the circadian variation in blood pressure is not influenced by the environment. Checking an unsatisfactory in-hospital ABPM with an outpatient recording may obviate the need for an (intensified) antihypertensive treatment in a substantial number of patients.

Prediction of peak exercise oxygen uptake by cardiopulmonary measurements at rest in heart transplant candidates.

OBJECTIVE: Peak oxygen uptake (VO2) is a powerful prognostic index, but maximal exercise testing in heart transplant candidates has a number of disadvantages. It is unknown whether it is possible to predict peak VO2 from a comprehensive dataset with parameters of heart and lung function at rest. METHODS: One hundred adult patients in sinus rhythm and with either idiopathic or ischaemic heart failure performed a graded cycle ergometer test until volitional fatigue and underwent radionuclide ventriculography, heart catheterization, and lung function measurements at rest. RESULTS: Weight, height, age, gender and aetiology of heart failure explained 48% of the variance of peak VO2. On top of these anthropometric, demographic and clinical patient characteristics, 12% of the variance of peak VO2 was additionally explained by all resting measurements combined, i.e. radionuclide left ventricular ejection fraction, peak ejection rate, peak filling rate, cardiac frequency, mean right atrial pressure, pulmonary capillary wedge pressure, pulmonary artery pressures, cardiac output, forced vital capacity, forced expiratory volume in one second, and pulmonary diffusing capacity (cumulative R2 = 0.60); among these, pulmonary vascular resistance was the most important predictor (+6%; P < 0.001). Analyses in a subset of 43 male patients pointed out that systemic pressures and vascular resistance were not related to peak VO2. CONCLUSION: On the basis of resting left ventricular function, haemodynamics, and routine pulmonary measurements, it is unlikely to accurately predict exercise tolerance in the majority of heart transplant candidates, i.e. patients with either idiopathic or ischaemic heart failure and able to exercise until exhaustion.

Late acute rejection and subclinical noncompliance with cyclosporine therapy in heart transplant recipients.

BACKGROUND: Although noncompliance with immunosuppressive medication is recognized as a critical behavioral risk factor for late acute rejection episodes and graft loss after transplantation, little is known about the degree of subclinical cyclosporine noncompliance, its associated risk for acute late rejection episodes (>1 year after transplantation), and its determinants in heart transplant recipients. METHODS: The convenience sample of this longitudinal study included 101 European heart transplant recipients (87 men and 14 women), with a median age of 56 (Q1 = 50, Q3 = 61) and a median posttransplantation status of 3 (range 1 to 6) years. Subclinical cyclosporine noncompliance was measured during a 3-month period with electronic event monitoring. Selected sociodemographic, behavioral, cognitive, emotional, health, and treatment-related determinants of medication noncompliance were measured by using instruments with established psychometric properties or by patient interviews. With the use of iterative partitioning methods of cluster analysis, including nonstandardized electronic event monitoring compliance parameters, patients were categorized by degree of subclinical cyclosporine noncompliance into a 3-cluster solution. RESULTS: Overall compliance was high, with a median medication taking compliance of 99.4%. The 3 derived clusters, that is, excellent compliers (84%), minor subclinical noncompliers (7%), and moderate subclinical noncompliers (9%), differed significantly by degree of subclinical noncompliance (p < .0001) and showed a 1.19%, 14.28%, and 22.22% incidence of late acute rejections (p = .01), respectively. The 3 groups also differed in terms of former medication noncompliance (p = .02), appointment noncompliance (p = .03), and perceived self-efficacy with medication taking (p = .04). CONCLUSIONS: Although in absolute numbers cyclosporine compliance in this sample was high, minor deviations from dosing schedule were associated with an increased risk for acute late rejection episodes. This suggests a pivotal role of patient compliance in successful long-term outcome after transplantation.

Prognostic assessment of end-stage cardiac failure.

Heart failure is not a disease, but rather a complex clinical syndrome that is growing in incidence and carries a very high morbidity and mortality. Although the incidence in the general adult population in the Western world is between 1% and 2%, the frequency increases rapidly in the elderly affecting more than 10% of the individuals over the age of 75 years. The treatment of patients with end-stage chronic heart failure (CHF) is difficult. The two major goals in the treatment of heart failure are to increase the duration (slow its progression) and quality of life (relief of symptoms). Understanding the severity of the syndrome of heart failure in terms of its prognosis can be particularly important in planning long-term management and in counselling the patient. The introduction of aggressive interventional therapies such as active haemodynamic support with ventricular assist devices, or heart transplantation emphasizes the importance of quantitating the risk of death in order to properly select patients for these more aggressive treatments. In large-scale trials it has been possible to identify markers that serve as significant predictors of mortality. Of these, the detection and quantification of neurohumoral activation have gained the most recent attention. Here, we discuss some of the prognostic tools in current use for heart failure patients and their applicability to patients with advanced heart failure.