Targeting Barriers of Systems of Care in a Growing Multi-disciplinary Field.

PURPOSE OF REVIEW: Cardio-oncology is a growing multi-disciplinary field that focuses on treating and preventing cardiovascular complications in cancer survivors and patients. This review summarizes the current clinical needs and system-based approaches to target barriers of care. RECENT FINDINGS: The field of cardio-oncology has experienced significant growth in recent years, and an increasing number of programs have been developed across the nation to provide improved and multi-disciplinary care to this patient population. Despite this burgeoning growth, practitioners in the field continue to face important challenges which include lack of administrative and departmental support, funding limitations, and gaps in the areas of mentoring, education, and research. Despite continued growth, cardio-oncology providers continue to face a multitude of challenges. Early inclusion of multi-disciplinary stakeholders, oncologists, cardiovascular team members, and administrative leadership provides an opportunity to collaborate and achieve unique patient care and health system benefits, such as prevention of adverse cardiovascular outcomes, and facilitates the delivery of optimal oncologic treatment.

Autoimmune Myocarditis Caused by Immune Checkpoint Inhibitors Treated With Antithymocyte Globulin.

The immune checkpoint inhibitors have brought about a paradigm shift in the treatment of many cancers and are being used as the first line therapy in increasing number of aggressive malignancies, including metastatic melanoma. Their adverse effects, mostly mediated by an uncontrolled overactivation of the immune system, may compromise the therapeutic benefit. Combination immune checkpoint therapies in particular, have higher therapeutic efficacy, but have also been associated with a higher incidence of severe immune-related adverse effects including autoimmune lymphocytic myocarditis. Recent clinical reports of this rare and life threatening condition indicated rapid progression of severe hemodynamic and electrical instability, with or without acute decompensated heart failure, reduced ejection fraction and shock, pointing to the need for early recognition, diagnosis and prompt management. Current guidelines for management of other immune-related adverse effects recommend high-dose glucocorticoids, with consideration of immunomodulators, such as infliximab in patients with severe colitis. However, knowledge about the treatment approaches in immune-related myocarditis remains extremely scarce. Here we report a case of severe, steroid refractory, lymphocytic myocarditis that occurred after the first cycle of combination immunotherapy with the programmed cell death protein-1 inhibitor, nivolumab, and the cytotoxic T-lymphocyte-associated protein 4 blocker, ipilimumab, for metastatic melanoma. We discuss treatment approaches including the role for transvenous pacemaker, advanced heart failure support, and interdisciplinary decision making.

Using Real World Evidence to Describe Pulmonary Arterial Hypertension Treatment Patterns, Healthcare Resource Utilization, and Costs Associated with PDE-5 Inhibitor Monotherapy.

Background: Pulmonary arterial hypertension (PAH) is described by proliferation of small pulmonary arteries leading to increased pulmonary vascular resistance, right ventricular failure, and death. Research confirms long-term improvement in composite morbidity and mortality endpoints on some endothelin receptor antagonists alone and in combination with phosphodiesterase type 5 inhibitors (PDE-5is) but not with PDE-5i monotherapy. While current treatment guidelines incorporate these findings, a substantial number of patients are started or maintained on PDE-5i monotherapy. Objectives: This study describes real-world clinical practice and treatment patterns with PDE-5i monotherapy including events indicative of clinical worsening, treatment modifications, adherence, allcause healthcare resource utilization, and costs. Methods: This retrospective study analyzed PharMetrics Plus claims data including 150 million lives; study period was January 1, 2009 through December 31, 2013. Eligible patients were ≥18 years with ≥1 inpatient or ≥2 outpatient claims ≥30 days apart, a diagnosis of pulmonary hypertension or other chronic pulmonary heart disease, and an initial PDE-5i prescription. To include only World Health Organization group 1 PAH patients, ≥1 encounter for right-heart catheterization or Doppler echocardiogram was required during the pre-index period. Results: PDE-5i monotherapy for PAH treatment was associated with high treatment modification rates, low adherence, increased healthcare resource utilization, and high costs. At 12 months post index, 41.5% of patients experienced treatment modification. For the index therapy, 47% of patients had ≥80% adherence to therapy. Almost 50% of patients had ≥1 hospitalization, with costs increased three fold to $197 111 compared to $59 164 for non-hospitalized patients. Conclusions: Initial treatment with PDE-5i monotherapy was associated with substantial direct medical costs, including hospitalizations and emergency department visits, low therapy adherence and a high rate of treatment modifications.

Secretome analysis of Trypanosoma cruzi by proteomics studies.

BACKGROUND: Chagas disease is a debilitating often fatal disease resulting from infection by the protozoan parasite Trypanosoma cruzi. Chagas disease is endemic in 21 countries of the Americas, and it is an emerging disease in other countries as a result of migration. Given the chronic nature of the infection where intracellular parasites persist for years, the diagnosis of T. cruzi by direct detection is difficult, whereas serologic tests though sensitive may yield false-positive results. The development of new rapid test based on the identification of soluble parasitic antigens in serum would be a real innovation in the diagnosis of Chagas disease. METHODS: To identify new soluble biomarkers that may improve diagnostic tests, we investigated the proteins secreted by T. cruzi using mass spectrometric analyses of conditioned culture media devoid of serum collected during the emergence of trypomastigotes from infected Vero cells. In addition, we compared the secretomes of two T. cruzi strains from DTU Tc VI (VD and CL Brener). RESULTS: Analysis of the secretome collected during the emergence of trypomastigotes from Vero cells led to the identification of 591 T. cruzi proteins. Three hundred sixty three proteins are common to both strains and most belong to different multigenic super families (i.e. TcS, GP63, MASP, and DGF1). Ultimately we have established a list of 94 secreted proteins, common to both DTU Tc VI strains that do not belong to members of multigene families. CONCLUSIONS: This study provides the first comparative analysis of the secretomes from two distinct T. cruzi strains of DTU TcVI. This led us to identify a subset of common secreted proteins that could potentially serve as serum markers for T. cruzi infection. Their potential could now be evaluated, with specific antibodies using sera collected from patients and residents from endemic regions.

Choosing Words Wisely in Communication With Patients With Heart Failure and Families.

The complex and often unpredictable course of heart failure (HF) provides many opportunities for communication between clinicians and patients about important subjects as advance care planning, disease state education, therapeutic options and limitations, and end-of-life care. Studies of patients with HF demonstrate that, when engaging in such complex communication, specific language matters in patient experience and in shared decision-making with providers. To date, clinical reports have outlined useful frameworks for communication with patients with HF but have not yet broached specific language crucial to furthering whole person care, particularly in the complex and emotional realm of advancing disease and transitions to end-of-life care. In this work, the investigators unpack language commonly used in advanced HF care and provide explicit suggestions to better provide such pivotal communication. In conclusion, specific phrasing may significantly impact patient experiences and outcomes. Communication that focuses on the disease itself and the therapy or intervention in question may help remove the patient from potential negative emotions, thus facilitating more objective shared decision-making with the clinician.

Combination therapy in pulmonary arterial hypertension: is this the new standard of care?

Pulmonary arterial hypertension (PAH) is a rare, progressive, and potentially fatal cardiopulmonary syndrome that imposes a significant burden on patients in terms of morbidity and mortality, and on managed care organizations in terms of resource utilization. The majority of PAH-approved therapies are high-touch, high-management, high-cost treatments dispensed through specialty pharmacies. Current treatment guidelines recommend combination therapy for patients who show inadequate clinical response or who deteriorate on monotherapy. Combination therapies target 2, or sometimes 3, distinct PAH-associated signaling pathways: the endothelin, prostacyclin, and nitric oxide pathways. Registry data suggest that combination therapy is utilized in more than half of patients with PAH in the United States. Evidence supporting the use of combination therapy is provided through clinical trials, retrospective research, registry data, and expert guidelines. Managed care decision makers are charged with making population-based decisions on resource allocation. These decision makers must always consider cost, but must also be aware that clinical evidence suggests that early treatment with combination therapy can significantly reduce disease burden, may reduce hospitalizations, and should be considered when making coverage decisions.

Associations among Depression Symptoms with Alcohol and Smoking Tobacco Use in Adult Patients with Congenital Heart Disease.

BACKGROUND: Adult congenital heart disease (ACHD) patients have high rates of untreated depression and anxiety disorders. We evaluated associations among self-reported depression symptoms and alcohol/smoking tobacco use. METHODS: From 2009 to 2013, 202 ACHD patients (45% male) completed questionnaires on depressive symptoms, anxiety symptoms, and substance use as part of routine clinical care. Data were collected by retrospective chart review. RESULTS: Mean age was 31 ± 10 years, 21% reported often feeling depressed and 33% reported feeling nervous or anxious. Sixty-one percent of patients reported some alcohol intake; 25% reported current or previous smoking tobacco use. Patients with depressive symptoms were 3× as likely to report drinking alcohol (OR 2.89; 95% CI 1.29-6.5) and 5× more likely to report smoking tobacco use (OR 5.17; 95% CI 1.49-17.87). Fourteen percent of patients were prescribed antidepressant/antianxiety medications; 43% of patients on medication reported depressive symptoms. In patients reporting symptoms, those who consumed alcohol were less likely to be on antidepressant/antianxiety medications (21%) than those who did not consume alcohol (56%). CONCLUSION: Self-reported depressive symptoms are associated with increased alcohol and smoking tobacco use by ACHD patients. Alcohol use may be a means of self-medicating for untreated depression, but further investigation is needed. Risk factors, including depressive symptoms and substance use, should be routinely assessed and addressed in ACHD patients.

Hospital readmission in heart failure, a novel analysis of a longstanding problem.

Acute decompensated heart failure is a significant source of morbidity and mortality in the USA. It is the most common reason for admission in the Medicare population and the greatest cause of hospital readmission in both medical and surgical patients. As many of these readmissions are considered preventable, providers and hospital systems are seeking novel strategies to reduce rehospitalization. Several specific interventions have been shown to decrease readmission for heart failure. However, these are typically narrow in scope, focusing on one aspect of patient care and providing a one-size-fits-all approach. We review the data and propose integrating some of these interventions into a comprehensive patient-centered model that is organized into six categories: quality of medical management, early reassessment, health literacy, neuropsychological status, financial means and functional status. By screening for deficiencies in each of these categories, providers and hospital systems can use resources more efficiently to make targeted interventions to improve health outcomes and mitigate readmissions.

Data-driven decisions for reducing readmissions for heart failure: general methodology and case study.

BACKGROUND: Several studies have focused on stratifying patients according to their level of readmission risk, fueled in part by incentive programs in the U.S. that link readmission rates to the annual payment update by Medicare. Patient-specific predictions about readmission have not seen widespread use because of their limited accuracy and questions about the efficacy of using measures of risk to guide clinical decisions. We construct a predictive model for readmissions for congestive heart failure (CHF) and study how its predictions can be used to perform patient-specific interventions. We assess the cost-effectiveness of a methodology that combines prediction and decision making to allocate interventions. The results highlight the importance of combining predictions with decision analysis. METHODS: We construct a statistical classifier from a retrospective database of 793 hospital visits for heart failure that predicts the likelihood that patients will be rehospitalized within 30 days of discharge. We introduce a decision analysis that uses the predictions to guide decisions about post-discharge interventions. We perform a cost-effectiveness analysis of 379 additional hospital visits that were not included in either the formulation of the classifiers or the decision analysis. We report the performance of the methodology and show the overall expected value of employing a real-time decision system. FINDINGS: For the cohort studied, readmissions are associated with a mean cost of $13,679 with a standard error of $1,214. Given a post-discharge plan that costs $1,300 and that reduces 30-day rehospitalizations by 35%, use of the proposed methods would provide an 18.2% reduction in rehospitalizations and save 3.8% of costs. CONCLUSIONS: Classifiers learned automatically from patient data can be joined with decision analysis to guide the allocation of post-discharge support to CHF patients. Such analyses are especially valuable in the common situation where it is not economically feasible to provide programs to all patients.

Impaired exercise capacity following atrial septal defect closure: an invasive study of the right heart and pulmonary circulation.

Patients with early repair of an isolated atrial septal defect (ASD) are expected to have unremarkable right ventricular (RV) and pulmonary circulation physiology. Some studies, however, suggest persistent functional impairment. We aimed to examine the role of abnormal RV and pulmonary vascular response to exercise in patients who had undergone ASD closure. Using a previously published data set, we reviewed invasive exercise cardiopulmonary testing with right-sided hemodynamic data for 12 asymptomatic patients who had undergone ASD closure. The 5 (42%) patients with impaired maximal oxygen uptake ([Formula: see text]) were older and exhibited a lower peak cardiac index (5.6 ± 0.8 vs. 9.0 ± 1.2 L/min/m(2); P = .005) because of abnormal stroke volume augmentation (+3.2 ± 3.9 vs. +17.4 ± 10.2 mL/m(2); P = .02). While all resting hemodynamic variables were similar, patients with low [Formula: see text] tended to have abnormal total pulmonary vascular resistance change during exercise (+11% ± 41% vs. -28% ± 26%; P = .06) and had a steeper relation between mean pulmonary arterial pressure and cardiac index (5.8 ± 0.6 vs. 2.2 ± 0.1 L/min/m(2); P = .02). The increase in peak mean RV power during exercise was also significantly lower in the impaired-[Formula: see text] patients (4.7 ± 1.6 vs. 7.6 ± 2.1 J/s; P = .04). As described in the original study, despite normal resting hemodynamics, a subset of asymptomatic patients with repaired ASD had diminished exercise capacity. Our analysis allows us to conclude that this is due to a combination of abnormal pulmonary vascular response to exercise and impaired RV function.

Intravenous Epoprostenol for Management of Pulmonary Arterial Hypertension during Pregnancy.

Background Pulmonary arterial hypertension carries a high risk of mortality in pregnancy. Recent advances in treatment may improve disease course and allow for successful management of the pregnancy. Case Report We present the case of a 20-year-old gravida 1, para 0 with diagnosis of severe primary pulmonary hypertension. The patient was managed with epoprostenol (prostacyclin) infusion via an indwelling catheter, which was initiated at 23 weeks' gestation. The dose was adjusted to the patient's symptoms and a successful vaginal delivery was achieved at 36 weeks' gestation. Although maternal postpartum course was uncomplicated, unexplained neonatal demise occurred at 11 days of life. Conclusion Successful management of pulmonary hypertension in pregnancy can be accomplished with a multidisciplinary approach and intensive therapy. Long-term effects of epoprostenol on fetal or neonatal well-being are unknown.

Isolation, culture, and identification of amniotic fluid-derived mesenchymal stem cells.

Amniotic fluid-derived mesenchymal stem cells (AF-MSC) are newly described, excellent seed cells that have good differentiation capability and are convenient to obtain. However, it is important to develop a method to isolate and culture AF-MSC efficiently. Amniotic fluid samples were obtained from rabbits and the adherence method was used for AF-MSC culture. Flow cytometry, western blot, and immunofluorescence studies were used to analyze the phenotypic characteristics of the cultured AF-MSC. Amniotic fluid-derived mesenchymal stem cells were successfully isolated and cultured from amniotic fluid. Flow cytometric analysis demonstrated that these cells expressed CD29 and CD44, while they did not express CD34. The expression of transcription factor Oct-4 was confirmed by western blot and immunofluorescence analysis. Using the adherence method, we developed a successful, reproducible protocol for the isolation of AF-MSC from amniotic fluid. The results of our phenotypic analysis revealed that the AF-MSC isolated in the present study were multipotent cells.

The effect of c-fos on acute myocardial infarction and the significance of metoprolol intervention in a rat model.

Over-expression of c-fos may play a role in some diseases. Research pertaining to the expression of c-fos in acute myocardial infarction (AMI) is rare, and the detailed role of c-fos in AMI has not been reported. Therefore, the purpose of this project was to elucidate the detailed effect of c-fos on AMI rats and evaluate the effect of a metoprolol intervention. An AMI rat model was established for the purposes of this study. The expression of c-fos in AMI was evaluated via immunohistochemical analysis and in situ hybridization. Simultaneously, we investigated the effect of c-fos on AMI rats via medicinal treatment with c-fos monoclonal antibody, isoproterenol, and metoprolol. Positive c-Fos protein expression and c-fos mRNA expression in cardiomyocytes were increased at 1, 3, 7, and 10 days after ligation in AMI rats compared with a sham-operated group. Peak expression occurred at 3 days after ligation. The weight percentage fraction of infarct size was decreased in rats treated with c-fos monoclonal antibody compared with the control normal saline treatment group. The weight percentage fraction of infarction size was increased after c-fos was increased via the administration of isoproterenol. c-Fos protein expression and the infarct size in rats treated with metoprolol were also decreased compared with the control normal saline treatment group. The results showed that c-fos expression rapidly increased after coronary ligation; c-fos plays an important role in myocardial lesions and is likely to be involved in the pathogenesis of AMI as well. Metoprolol can inhibit the expression of c-fos and has a positive therapeutic effect on rats after AMI; the involvement effect of metoprolol on myocardial infarction might be correlated with its effect on the inhibition of c-fos.

Role of the JAK/STAT signaling pathway in the pathogenesis of acute myocardial infarction in rats and its effect on NF-κB expression.

The Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT signaling pathway) is involved in the development of numerous cardiovascular diseases, although the specific role of this pathway in the pathogenesis of acute myocardial infarction (AMI) has not been elucidated. The purpose of this study was to evaluate the role of the JAK/STAT signaling pathway in the onset of AMI in rats. We also tested the effect of this pathway on nuclear factor κB (NF-κB) expression in the myocardium and tumor necrosis factor-α (TNF-α) levels in the plasma of AMI rats. An AMI rat model was successfully established and AG490 was used to block the JAK/STAT signaling pathway. The plasma TNF-α levels of AMI rats were measured by ELISA. The protein expression of NF-κB in the myocardial cells of AMI rats was detected by immunohistochemistry. The infarction area was significantly smaller in rats treated with AG490 after coronary artery ligation (group C) compared with that in the myocardial infarction control group (group B). The left ventricular mass indices in the sham surgery group (group A) and group C were significantly lower compared with those of group B. Plasma TNF-α concentrations in group B were significantly higher compared with those of groups A and C. There were significantly fewer cardiomyocytes positively exhibiting NF-κB protein expression in groups A and C compared with group B. The JAK/STAT signaling pathway is involved in the onset of myocardial infarction and may also be involved in left ventricular remodeling after myocardial infarction. The involvement of the JAK/STAT signaling pathway in the onset of myocardial infarction may be correlated with its effects on the expression of NF-κB and TNF-α.

Changes in adiponectin expression in acute myocardial infarction rats and the significance of bisoprolol intervention.

The aims of this study were to explore the changes in expression of myocardial adiponectin (APN), changes in serum APN, and the significance of bisoprolol intervention in acute myocardial infarction (AMI) rats. An AMI rat model was established for the purposes of this study and was used for analysis of serum APN as determined by ELISA. Changes in expression of myocardial APN mRNA and APN protein in AMI rats were determined via reverse transcriptase (RT)-PCR and immunohistochemistry. Serum APN concentration and APN protein expression of the myocardium decreased significantly in the AMI groups compared with the sham operation group, with the lowest serum APN and APN protein expression on day 7 after AMI. On days 7 and 10 after AMI, the expression of myocardial APN mRNA in the AMI groups decreased significantly compared with the sham operation group. However, the APN mRNA increased on day 10 compared with that on day 7. Notably, there was an increase in levels of serum APN and myocardial APN expression after bisoprolol intervention. The expression of myocardial APN and serum APN decreased in AMI rats. APN may be an important protective factor against AMI. Bisoprolol can also protect against AMI because it increases APN expression.

The expression and significance of proto-oncogene c-fos in viral myocarditis.

BACKGROUND: c-fos may play a role in the pathogenesis of some diseases. The expression and function of c-fos in viral myocarditis (VMC) have not yet been reported. To study the change and significance of proto-oncogene c-fos in VMC is the objective of this experiment. METHODS: An animal model of VMC was established via coxsackie virus B3 inoculation. VMC mice were then treated with a c-fos monoclonal antibody and isoproterenol and the protein and mRNA expression of c-fos were studied via immunohistochemical analysis and in situ hybridization. Results were simultaneously analyzed for the significance of c-fos expression in mice with VMC. RESULTS: Myocardial necrosis and cell infiltration decreased after treatment with c-fos monoclonal antibody compared to control mice, while myocardial necrosis and cell infiltration were increased after treatment with isoproterenol. Positive cardiomyocytes with c-Fos expression increased at 3, 5, 7, 9, and 15 days after virus inoculation in VMC mice compared to control mice, while returning to almost normal levels at 35 days. The expression level of c-fos mRNA at 3 and 7 days after virus inoculation in VMC mice was also higher than that of control mice. CONCLUSIONS: c-fos expression in the cardiomyocytes of VMC mice is significantly increased, c-fos plays an important role in myocardial lesions. The apparent increase in expression of c-fos is likely to be involved in the pathogenesis of VMC.

Prolonged cold ischemia: risk factor for acute rejection in renal grafting of cadaveric kidney transplantation.

BACKGROUND: Exposure of renal grafting to prolonged cold ischemia time (CIT) and the association with acute rejection (AR) are known. However, there is no evidence in Mexico about this topic. Thus, the objective of this study was to evaluate prolonged CIT as a risk factor for AR in renal grafting of cadaveric kidney transplantation in a Mexican population. METHODS: A cross-sectional study was carried out. Clinical files of patients undergoing renal grafting using cadaveric kidneys were reviewed from July 1994-June 2004. Prolonged CIT (=12 h) as a risk factor for AR was evaluated. Other related variables were also examined. RESULTS: From 425 kidney transplantations, only 33 cases were cadaveric. Ten patients had AR. Prolonged CIT (OR 8.4; CI 1.5-44.2, p = 0.02) and azathioprine (AZA)-prednisone (PDN)-cyclosporine (CSA) combination (OR 9.1; CI 1.5-49.4, p = 0.02) were risk factors for AR. Anti-CD25 use (OR 0.6; CI 0.009-0.37, p = 0.001) and mycofenolate mofetil (MMF)-PDN-CSA combination (OR 0.1; CI 0.02-0.65, p = 0.02) were protective factors for AR. CONCLUSIONS: In a Mexican population, prolonged CIT and AZA-PDN-CSA combination were risk factors for AR. Meanwhile, anti- CD25 use and MMF-PDN-CSA combination were protective factors for AR in cadaveric kidney transplantations.