Clinical Correlates of a Nonplexiform Vasculopathy in Patients With a Diagnosis of Idiopathic Pulmonary Arterial Hypertension.

BACKGROUND: The clinical phenotype of idiopathic pulmonary arterial hypertension (IPAH) patients has changed. Whether subgroups of patients with IPAH have different vascular phenotypes is a subject of debate. RESEARCH QUESTION: What are the histologic patterns and their clinical correlates in patients with a diagnosis of IPAH or hereditary pulmonary arterial hypertension (PAH)? STUDY DESIGN AND METHODS: In this this cross-sectional registry study, lung histologic examination of 50 patients with IPAH was assessed qualitatively by two experienced pathologists. In addition, quantitative analysis by means of histopathologic morphometry using immunohistochemistry was performed. Histopathologic characteristics were correlated with clinical and hemodynamic parameters. RESULTS: In this cohort of 50 patients with IPAH, a plexiform vasculopathy was observed in 26 of 50 patients (52%), whereas 24 of 50 patients (48%) showed a nonplexiform vasculopathy. The nonplexiform vasculopathy was characterized by prominent pulmonary microvascular (arterioles and venules) remodeling and vascular rarefaction. Although hemodynamic parameters were comparable in plexiform vs nonplexiform vasculopathy, patients with nonplexiform vasculopathy were older, more often were male, had a stronger history of cigarette smoking, and lower diffusing capacity of the lungs for carbon monoxide (Dlco) at diagnosis. No mutations in established PAH genes were found in the nonplexiform group. INTERPRETATION: This study revealed different vascular phenotypes within the current spectrum of patients with a diagnosis of IPAH, separated by clinical characteristics (age, sex, history of cigarette smoking, and Dlco at diagnosis). Potential differences in underlying pathobiological mechanisms between patients with plexiform and nonplexiform microvascular disease should be taken into account in future research strategies unravelling the pathophysiologic features of pulmonary hypertension and developing biology-targeted treatment approaches.

Molecular mechanisms and targets of right ventricular fibrosis in pulmonary hypertension.

Right ventricular fibrosis is a stress response, predominantly mediated by cardiac fibroblasts. This cell population is sensitive to increased levels of pro-inflammatory cytokines, pro-fibrotic growth factors and mechanical stimulation. Activation of fibroblasts results in the induction of various molecular signaling pathways, most notably the mitogen-activated protein kinase cassettes, leading to increased synthesis and remodeling of the extracellular matrix. While fibrosis confers structural protection in response to damage induced by ischemia or (pressure and volume) overload, it simultaneously contributes to increased myocardial stiffness and right ventricular dysfunction. Here, we review state-of-the-art knowledge of the development of right ventricular fibrosis in response to pressure overload and provide an overview of all published preclinical and clinical studies in which right ventricular fibrosis was targeted to improve cardiac function.

Correction to: The Sydney Heart Bank: improving translational research while eliminating or reducing the use of animal models of human heart disease.

In the original version of this article, the name of one of the authors is not correct. The correct name should be W. A. Linke, which is shown correctly in the authorgroup section above.

The Sydney Heart Bank: improving translational research while eliminating or reducing the use of animal models of human heart disease.

The Sydney Heart Bank (SHB) is one of the largest human heart tissue banks in existence. Its mission is to provide high-quality human heart tissue for research into the molecular basis of human heart failure by working collaboratively with experts in this field. We argue that, by comparing tissues from failing human hearts with age-matched non-failing healthy donor hearts, the results will be more relevant than research using animal models, particularly if their physiology is very different from humans. Tissue from heart surgery must generally be used soon after collection or it significantly deteriorates. Freezing is an option but it raises concerns that freezing causes substantial damage at the cellular and molecular level. The SHB contains failing samples from heart transplant patients and others who provided informed consent for the use of their tissue for research. All samples are cryopreserved in liquid nitrogen within 40 min of their removal from the patient, and in less than 5-10 min in the case of coronary arteries and left ventricle samples. To date, the SHB has collected tissue from about 450 failing hearts (>15,000 samples) from patients with a wide range of etiologies as well as increasing numbers of cardiomyectomy samples from patients with hypertrophic cardiomyopathy. The Bank also has hearts from over 120 healthy organ donors whose hearts, for a variety of reasons (mainly tissue-type incompatibility with waiting heart transplant recipients), could not be used for transplantation. Donor hearts were collected by the St Vincent's Hospital Heart and Lung transplantation team from local hospitals or within a 4-h jet flight from Sydney. They were flushed with chilled cardioplegic solution and transported to Sydney where they were quickly cryopreserved in small samples. Failing and/or donor samples have been used by more than 60 research teams around the world, and have resulted in more than 100 research papers. The tissues most commonly requested are from donor left ventricles, but right ventricles, atria, interventricular system, and coronary arteries vessels have also been reported. All tissues are stored for long-term use in liquid N or vapor (170-180 °C), and are shipped under nitrogen vapor to avoid degradation of sensitive molecules such as RNAs and giant proteins. We present evidence that the availability of these human heart samples has contributed to a reduction in the use of animal models of human heart failure.

Pneumonectomy combined with SU5416 induces severe pulmonary hypertension in rats.

The SU5416 + hypoxia (SuHx) rat model is a commonly used model of severe pulmonary arterial hypertension. While it is known that exposure to hypoxia can be replaced by another type of hit (e.g., ovalbumin sensitization) it is unknown whether abnormal pulmonary blood flow (PBF), which has long been known to invoke pathological changes in the pulmonary vasculature, can replace the hypoxic exposure. Here we studied if a combination of SU5416 administration combined with pneumonectomy (PNx), to induce abnormal PBF in the contralateral lung, is sufficient to induce severe pulmonary arterial hypertension (PAH) in rats. Sprague Dawley rats were subjected to SuPNx protocol (SU5416 + combined with left pneumonectomy) or standard SuHx protocol, and comparisons between models were made at week 2 and 6 postinitiation. Both SuHx and SuPNx models displayed extensive obliterative vascular remodeling leading to an increased right ventricular systolic pressure at week 6 Similar inflammatory response in the lung vasculature of both models was observed alongside increased endothelial cell proliferation and apoptosis. This study describes the SuPNx model, which features severe PAH at 6 wk and could serve as an alternative to the SuHx model. Our study, together with previous studies on experimental models of pulmonary hypertension, shows that the typical histopathological findings of PAH, including obliterative lesions, inflammation, increased cell turnover, and ongoing apoptosis, represent a final common pathway of a disease that can evolve as a consequence of a variety of insults to the lung vasculature.

How to diagnose heart failure with preserved ejection fraction: the value of invasive stress testing.

Heart failure with preserved ejection fraction (HFpEF) is a growing healthcare burden worldwide and its prevalence is increasing. Diagnosing HFpEF is challenging and relies upon the presence of symptoms and/or signs of heart failure, preserved left ventricular systolic function, and evidence of diastolic dysfunction. Current diagnostic algorithms mainly rely on echocardiography (E/e') and biomarkers (NT-proBNP). However, only a minority of patients with HFpEF are identified, and especially HFpEF patients at an early stage of the disease are easily missed. We propose to incorporate invasive stress testing, by means of right heart catheterisation at rest and during exercise, and accurate assessment of right ventricular function, by means of cardiac magnetic resonance imaging. These additions to the current diagnostic work-up will improve diagnostic sensitivity and accurate staging of HFpEF patients.

Drug-drug interactions in patients treated for cancer: a prospective study on clinical interventions.

BACKGROUND: Drug-drug interactions (DDIs) are of major concern in oncology, since cancer patients typically take many concomitant medications. Retrospective studies have been conducted to determine the prevalence of DDIs. However, prospective studies on DDIs needing interventions in cancer patients have not yet been carried out. Therefore, a prospective study was designed to identify DDIs leading to interventions among ambulatory cancer patients receiving anticancer treatment. PATIENTS AND METHODS: Patients starting with a new treatment regimen with i.v. or oral anticancer medication were asked to participate. The patients' medication was checked for DDIs by using drug interaction software. An expert team of clinical pharmacologists evaluated the relevance of these identified DDIs. If a DDI was qualified as potentially clinically relevant, an intervention was proposed to the treating (hemato)oncologist. Several variables were studied as determinants for performing an intervention. Descriptive statistics and uni- and multivariate logistic regression analyses were carried out. RESULTS: In this study, 302 patients were included. A total of 603 DDIs were identified by the drug interaction software and judged by the expert team. Of all 603 DDIs, 120 DDIs were considered potentially clinically relevant. These 120 DDIs, present in a total of 81 patients, resulted in a clinical intervention already executed by the (hemato)oncologist in 39 patients (13%), while an additional intervention was proposed by a clinical pharmacologist in 42 patients (14%). The number of comorbidities and the number of 'over-the-counter' drugs were identified as determinants. CONCLUSIONS: Clinical interventions on DDIs are frequently required among patients starting with anticancer therapy. Structured screening for these potentially clinically relevant DDIs, by (hemato)oncologists in close collaborations with clinical pharmacologists, should take place before the start and during anticancer treatment. CLINICAL TRIALS NUMBER: This study was registered at the Dutch Trial Registry under number NTR3760.

Minimal effects on ex vivo coagulation during mild therapeutic hypothermia in post cardiac arrest patients.

OBJECTIVES: Mild therapeutic hypothermia (MTH) is being used to improve neurological outcome and survival in patients successfully resuscitated after cardiac arrest. The impact on coagulation may be difficult to assess since most coagulation parameters are measured at 37°C and not at actual body core temperature. Therefore we investigated the effects of MTH both at body core (target) temperature of 32°C and at 37°C. METHODS: Patients admitted at the ICU after cardiac arrest treated with MTH. Baseline blood samples, measured at 37°C were taken directly at arrival. The second and third samples were drawn within 1h and 24h after reaching target temperature and were measured at 32°C and 37°C. A final sample was drawn when the patient returned to normotemperature (measured at 37°C). Clotting time (CT) and maximum clotting formation (MCF) were measured with thromboelastometry. RESULTS: Upon reaching target temperature (32°C) Extem and Intem CT were increased compared to baseline with 57s (49-75) to 65s (59-72) and 165s (144-183) to 193s (167-212) respectively (median with IQR; P<0.05), with a further significant increase after 24h of hypothermia with 68s (57-80) and 221s (196-266). Samples analyzed at 32°C showed a significant longer CT of 12s in Extem and 33s in Intem compared to 37°C. MCF was not affected by MTH or adjustment of temperature. CONCLUSION: The mild effect of MTH on coagulation parameters remains unidentified when measured at 37°C. Although measurements at 32°C differ from those at 37°C, this does not appear to be of clinical relevance as all values were still within the reference range.

The effect of audible alarms on anaesthesiologists' response times to adverse events in a simulated anaesthesia environment: a randomised trial.

Alarms are ubiquitous in anaesthetic practice, but their net effect on anaesthesiologists' performance and patient safety is debated. In this study, 27 anaesthesiologists performed two simulation sessions in random order; one session was programmed to include an alarm condition, with a standard, frequent, clearly audible alarm sound. During these sessions, adverse events were simulated and anaesthesiologists' response times to these events were recorded. Perceived workload was assessed with the NASA Task Load Index. Response times to adverse events and perceived workload were similar in both groups. Pooled response times to atrial fibrillation and desaturation were fast, with a median (range [IQR]) of 8 (4-14 [1-41]) s and 9 (6-16 [1-44]) s, respectively. Pooled response times to an ST segment elevation on the ECG and an obstructed intravenous line were significantly slower, with median (IQR[range]) times of 34 (21-76[4-300]) s and 227 (95-399 [2-600]) s, respectively (p < 0.001). This study shows that in a simulated anaesthesia environment, response times to adverse events are similar in the absence or presence of an audible alarm, and that response times to various critical events differ.

Pressure-overload-induced right heart failure.

Although pulmonary arterial hypertension originates in the lung and is caused by progressive remodeling of the small pulmonary arterioles, patients die from the consequences of pressure-overload-induced right heart failure. Prognosis is poor, and currently there are no selective treatments targeting the failing right ventricle. Therefore, it is of utmost importance to obtain more insights into the mechanisms of right ventricular adaptation and the transition toward right heart failure. In this review, we propose that the same adaptive mechanisms, which initially preserve right ventricular systolic function and maintain cardiac output, eventually initiate the transition toward right heart failure.

Arthrodesis of the knee following failed arthroplasty.

PURPOSE: Primary stability in arthrodesis of the knee can be achieved by external fixation, intramedullary nailing or plate fixation. Each method has different features and results. We present a practical algorithm for arthrodesis of the knee following a failed (infected) arthroplasty, based on our own results and a literature review. METHODS: Between 2004 and 2010, patients were included with an indication for arthrodesis after failed (revision) arthroplasty of the knee. Patients were analyzed with respect to indication, fusion method and bone contact. End-point was solid fusion. RESULTS: Twenty-six arthrodeses were performed. Eighteen patients were treated because of an infected arthroplasty. In total, ten external fixators, ten intramedullary nails and six plate fixations were applied; solid fusion was achieved in 3/10, 8/10 and 3/6, respectively. CONCLUSIONS: There is no definite answer as to which method is superior in performing an arthrodesis of the knee. Intramedullary nailing achieved the best fusion rates, but was used most in cases without--or cured--infection. Our data and the contemporary literature suggest that external fixation can be abandoned as standard fusion method, but can be of use following persisting infection. The Ilizarov circular external fixator, however, seems to render high fusion rates. Good patient selection and appropriate individual treatment are the key to a successful arthrodesis. Based upon these findings, a practical algorithm was developed.

Intra-operative monitoring--many alarms with minor impact.

Alarms are key components of peri-operative monitoring devices, but a high false-alarm rate may lead to desensitisation and neglect. The objective of this study was to quantify the number of alarms and assess the value of these alarms during moderate-risk surgery. For this purpose, we analysed documentation of anaesthesia workstations during 38 surgical procedures. Alarms were classified on technical validity and clinical relevance. The median (IQR [range]) alarm density per procedure was 20.8 (14.5-34.2 [3.7-85.6]) alarms.h⁻¹ (1 alarm every 2.9 min) and increased during induction and emergence of anaesthesia, with up to one alarm per 0.99 min during these periods (p < 0.001). Sixty-four per cent of all alarms were clinically irrelevant, whereas 5% of all alarms required immediate intervention. The positive predictive value of an alarm during induction and emergence was 20% (95% CI 16-24%) and 11% (95% CI 8-14%), respectively. This study shows that peri-operative alarms are frequently irrelevant, with a low predictive value for an emerging event requiring clinical intervention.

Approaches for non-invasive assessment of endothelial function: focus on peripheral arterial tonometry.

The arterial endothelium is a complex organ that modulates vascular tone by release of various substances to control perfusion. Endothelial function reflects vascular ageing and health. Already at the earliest stages of atherosclerosis the delicate balance between arterial constriction and relaxation is disturbed. Therefore, non-invasive assessment of endothelial function is a means to identify patients at increased cardiovascular risk, even at levels of disease that cannot be identified with classical imaging techniques that depict arterial wall and/or lumen or with functional assessment of ischaemia. Currently, there is an increasing interest in the early recognition of endothelial dysfunction to streamline and optimise preventive therapeutic measures. In this article, several methods for the assessment of endothelial function are briefly reviewed. In particular, we discuss the fast bed-side assessment of endothelial function by the reactive hyperaemia peripheral arterial tonometry (RH-PAT) method.

[Aging and hyponutrition; a challenge for the sustainability of the NHS. Conclusions of the 9th ABBOT-SENPE Debate Forum]. / Envejecimiento y desnutrición; un reto para la sostenibilidad del SNS; conclusiones del IX Foro de Debate Abbott-SENPE.

Hyponutrition is a common problem at all health care levels, from primary to specialized care, as well as in geriatric care. Its incidence in a hospital setting is 40% and 60% in nursing homes. This is very important, it is highly related with progressive aging of the European population, and is the biggest and most frequent cause of disability among the elderly population living at home or institutions. Countries such as Holland, Denmark, or the United Kingdom have developed Comprehensive Strategic Plans to fight against hyponutrition by developing and implementing guidelines, establishing mandatory screenings at the moment of hospital admission and discharge, at nursing homes, etc. In our country, a combined action of SENPE and Abbott Foundation is developing a Comprehensive Strategic Plan (+ nutridos Project) in which clear, precise, and validated recommendations are established to perform nutritional screening both in hospitalized patients and institutionalized and ambulatory elderly people. This issue has to take into account the social and financial aspects. Hyponutrition is many times insufficiently recognized and treated. This has a negative impact on the individual patient in terms of morbidity, mortality, independence, and quality of life, as well as on the health care systems in terms of use of health care resources and costs.

Envejecimiento y desnutrición; un reto para la sostenibilidad del SNS; conclusiones del IX Foro de Debate Abbott-SENPE / Aging and hyponutrition; a challenge for the sustainability of the NHS. Conclusions of the 9th ABBOT-SENPE Debate Forum

La desnutrición es un problema común en todos los niveles de atención sanitaria, desde atención primaria a especializada y en centros de atención geriátrica. Su incidencia en los hospitales es del 40% y en las residencias de mayores supera el 60%. Esto último es de gran importancia, tienen una alta relación con el progresivo envejecimiento de la población europea, y es la mayor y más frecuente causa de discapacidad en la población anciana que vive en su domicilio o en instituciones. Países como Holanda, Dinamarca o el Reino Unido han desarrollado Planes Estratégicos Integrales para luchar contra la desnutrición desarrollando e implantando guías, estableciendo cribados obligatorios en los ingresos y altas hospitalarias, en las residencias en ancianos, etc. En nuestro país, en una acción conjunta de SENPE y la Fundación Abbott, estamos desarrollando un Plan Estratégico Integral (Proyecto + nutridos) en el que establecemos recomendaciones claras, precisas y validadas para efectuar cribaje nutricional tanto en pacientes hospitalizados, como en los institucionalizados y en los mayores ambulatorios. En este tema deben de ser tenidos en cuenta los aspectos sociales y financieros. La desnutrición es con mucha frecuencia deficientemente reconocida y tratada. Ello tiene un impacto negativo sobre los pacientes individuales en términos de morbilidad, mortalidad, independencia y calidad de vida, y sobre los sistemas de cuidado sanitario en términos de uso de recursos y costes (AU)

Hyponutrition is a common problem at all health care levels, from primary to specialized care, as well as in geriatric care. Its incidence in a hospital setting is 40% and 60% in nursing homes. This is very important, it is highly related with progressive aging of the European population, and is the biggest and most frequent cause of disability among the elderly population living at home or institutions. Countries such as Holland, Denmark, or the United Kingdom have developed Comprehensive Strategic Plans to fight against hyponutrition by developing and implementing guidelines, establishing mandatory screenings at the moment of hospital admission and discharge, at nursing homes, etc. In our country, a combined action of SENPE and Abbott Foundation is developing a Comprehensive Strategic Plan (+ nutridos Project) in which clear, precise, and validated recommendations are established to perform nutritional screening both in hospitalized patients and institutionalized and ambulatory elderly people. This issue has to take into account the social and financial aspects. Hyponutrition is many times insufficiently recognized and treated. This has a negative impact on the individual patient in terms of morbidity, mortality, independence, and quality of life, as well as on the health care systems in terms of use of health care resources and costs (AU)

Severe prosthetic joint infection in an immunocompetent male patient due to a therapy refractory Pseudallescheria apiosperma.

Prosthetic joint infections (PJI) are rarely due to fungal agents and if so they are mainly caused by Candida strains. This case represents a PJI caused by a multi-drug resistant Pseudallescheria apiosperma, with poor in vivo response to itraconazole and voriconazole. This case differs also by the way of infection, since the joint infection did not follow a penetrating trauma. In the majority of cases, Scedosporium extremity infections remain local in immunocompetent individuals. We report a persistent joint infection with multiple therapeutic failures, and subsequent amputation of the left leg. Detailed clinical data, patient history, treatment regime and outcome of a very long-lasting (>4 years) P. apiosperma prosthetic knee infection in an immunocompetent, 61-year-old male patient are presented with this case. The patient was finally cured by the combination of multiple and extensive surgical interventions and prolonged antifungal combination therapy with voriconazole and terbinafine.

Diaphragm muscle fiber function and structure in humans with hemidiaphragm paralysis.

Recent studies proposed that mechanical inactivity of the human diaphragm during mechanical ventilation rapidly causes diaphragm atrophy and weakness. However, conclusive evidence for the notion that diaphragm weakness is a direct consequence of mechanical inactivity is lacking. To study the effect of hemidiaphragm paralysis on diaphragm muscle fiber function and structure in humans, biopsies were obtained from the paralyzed hemidiaphragm in eight patients with hemidiaphragm paralysis. All patients had unilateral paralysis of known duration, caused by en bloc resection of the phrenic nerve with a tumor. Furthermore, diaphragm biopsies were obtained from three control subjects. The contractile performance of demembranated muscle fibers was determined, as well as fiber ultrastructure and morphology. Finally, expression of E3 ligases and proteasome activity was determined to evaluate activation of the ubiquitin-proteasome pathway. The force-generating capacity, as well as myofibrillar ultrastructure, of diaphragm muscle fibers was preserved up to 8 wk of paralysis. The cross-sectional area of slow fibers was reduced after 2 wk of paralysis; that of fast fibers was preserved up to 8 wk. The expression of the E3 ligases MAFbx and MuRF-1 and proteasome activity was not significantly upregulated in diaphragm fibers following paralysis, not even after 72 and 88 wk of paralysis, at which time marked atrophy of slow and fast diaphragm fibers had occurred. Diaphragm muscle fiber atrophy and weakness following hemidiaphragm paralysis develops slowly and takes months to occur.

Evidence-based tailored conservative treatment of knee and hip osteoarthritis: between knowing and doing.

OBJECTIVE: Insufficient data are available on the efficacy of combined conservative interventions recommended by treatment guidelines for knee/hip osteoarthritis (OA). The aims of this observational cohort study were (i) to estimate the results of an evidence-based 12-week tailored multimodal conservative treatment protocol for patients with knee/hip OA and (ii) to identify predictors for response. METHODS: After obtaining data on previous OA-related interventions, multimodal treatment was offered to patients with knee and/or hip OA at a specialized outpatient clinic. Treatment with analgesics was tailored using a numeric rating scale (NRS) for pain, aiming for NRS ≤ 4. The following outcome measures were assessed: (i) the proportion of patients fulfilling OMERACT-OARSI (Outcome Measures in Rheumatoid Arthritis Clinical Trials/Osteoarthritis Research Society International) responder criteria and (ii) the proportion of patients with NRS pain ≤ 4 after 12 weeks. RESULTS: A total of 183 out of 299 patients was included. OMERACT-OARSI responder criteria were fulfilled at 12 weeks in 47% of patients; 39% reached NRS pain ≤ 4. The only independent predictor for response was the number of previously used non-steroidal anti-inflammatory drugs (NSAIDs). The majority of patients had not been exposed adequately to conservative treatment modalities for knee and/or hip OA in the past (81%). CONCLUSION: Evidence-based multimodal conservative treatment using a standardized protocol for knee and/or hip OA is feasible and successful in 47% of patients. In general, response could not be predicted. Basic first-line recommended conservative treatment options have not been used adequately prior to referral to secondary care in the vast majority of patients.