Cardiac Amyloidosis: A Contemporary Review of Medical and Surgical Therapy.

Amyloidosis is a systemic disease initiated by deposition of misfolded proteins in the extracellular space, due to which multiple organs may be affected concomitantly. Cardiac amyloidosis, however, remains a major cause of morbidity and mortality in this population due to infiltrative /restrictive cardiomyopathy. This review attempts to focus on contemporary medical and surgical therapies for the different types of cardiac amyloidosis. Amyloidosis affecting the heart are predominantly of the transthyretin type (acquired in the older or genetic in the younger patients), and the monoclonal immunoglobulin light chain (AL) type which is solely acquired. A rare form of secondary amyloidosis AA type can also affect the heart due to excessive production and accumulation of the acute-phase protein called Serum Amyloid A" (SAA) in the setting of chronic inflammation, cancers or autoinflammatory disease. More commonly AA amyloidosis is seen in the liver and kidney. Other rare types are Apo A1 and Isolated Atrial Amyloidosis (AANF). Medical therapies have made important strides in the clinical management of the two common types of cardiac amyloidosis. Surgical therapies such as mechanical circulatory support and cardiac transplantation should be considered in appropriate patients. Future research using AI driven algorithms for early diagnosis and treatment as well as development of newer genetic engineering technologies will drive improvements in diagnosis, treatment and patient outcomes.

Closing the Gap: Investigation of Various Approaches in the Management of Patent Ductus Arteriosus.

In preterm newborns with extremely low birth weights, patent ductus arteriosus (PDA), which is defined as a remnant connection between the aorta and pulmonary artery after 72 hours of birth, is frequently linked to substantial morbidity and mortality. If left untreated, a hemodynamically significant PDA (hsPDA) increases the risk for bronchopulmonary dysplasia, necrotizing enterocolitis, and intraventricular hemorrhage among other morbidities, and can even lead to death. While instances of patent ductus arteriosus (PDA) resolving on their own are frequent, the primary approach for managing PDA closure in premature infants involves pharmacological interventions, commonly utilizing indomethacin, ibuprofen, or paracetamol. However, with these pharmacological treatment options, there is an increased risk of renal toxicity, gastrointestinal bleeding, and reopening of PDA among other complications. If pharmacological interventions are not successful or contraindicated, PDA can be closed via transcatheter closure or surgical ligation. As with any medically invasive procedure, it is not without risks and can lead to long-term complications. This review explores the different management options and the benefits and outcomes of conservative management vs. active management in order to get one step closer to standardizing the treatment for PDA. With so much controversy surrounding the best management option, there is a lack of evidence to support one treatment method superior to the other in reducing overall mortality, and this needs to be explored further.

Effects of Methimazole vs Propylthiouracil in Newborns: A Comparative Review.

Hyperthyroidism is more common in women and the sensitivity of thyroid function changes during pregnancy. Excess levels of thyroid hormones and thioamides have a major impact on maternal and fetal outcomes. Our aim was to perform an extensive literature review and provide relevant details concerning the analytical and clinical aspects of the potential effects of the two main drugs used (methimazole and propylthiouracil) in newborns. A thorough literature review was conducted using PubMed and Google Scholar databases. In total, 10 relevant studies were identified and data from these studies were extracted and then extrapolated into results after analysis. Three out of four studies that used methimazole and carbimazole, one and two, respectively, showed adverse fetal outcomes requiring surgical management for congenital anomalies like aplasia cutis, patent vitellointestinal duct, and gastroschisis. Out of the three studies that used propylthiouracil, one baby underwent surgery for bilateral pyelectasis, vesicovaginal fistula, anal stenosis, and polydactyly. The findings of the aforementioned studies provide enough evidence to imply that the use of methimazole and carbimazole to treat antenatal hyperthyroidism has worse fetal outcomes than the use of propylthiouracil. Also, given the paucity of data in the existing literature regarding propylthiouracil's effects on newborns, further studies in this demographic are needed.

Skin Cancer Risk Prediction in Heart Transplant Recipients.

OBJECTIVES: This study was undertaken to derive a risk prediction model for skin cancer utilizing the United Network for Organ Sharing database population. MATERIALS AND METHODS: Of the 24734 adults (>18 years old) heart transplant recipients (2000-2015) in the United Network for Organ Sharing database, 2625 recipients developed skin cancer. Univariate and multivariate Cox regression analyses were performed; P values, hazard ratios, and confidence intervals were derived. The model was tested using receiver operating characteristics curves and area under the curves. MATLAB software (MathWorks) was used for analyses. RESULTS: Multivariate analysis showed that White patients had a hazard ratio of 31.7 compared with Black patients (P < .001). Male patients had a hazard ratio of 2.52 (P < .001) compared with female patients. Malignancy at listing showed a hazard ratio of 1.77 (P < .001). Thymoglobulin had a hazard ratio of 1.19 (P = .005) compared with other induction agents. The receiver operating characteristic curves generated for 5 years, 8 years, and 10 years after transplant showed area under the curve values of 0.78, 0.77, and 0.76, respectively, in the training set and 0.75, 0.75, and 0.74, respectively, in the validation set. CONCLUSIONS: Male sex, White ethnicity, older age, malignancy at the time of listing or at time of transplant, and thymoglobulin induction are major risk factors for skin cancers after transplant. This risk prediction model has a C statistic of 0.75. To our knowledge,this is the firsttime such a model has been generated for skin cancers in this population.

Covaxin-Induced Lymphocytic Myocarditis.

We report the case of a young adult male with endomyocardial biopsy-proven lymphocytic myocarditis following Covaxin administration. Covaxin differs from the mRNA vaccines in that it is an inactivated virus developed using the whole virion inactivated using the Vero cell platform. We successfully managed the patient with complete resolution of symptoms.

Role of the Gut in the Temporal Changes of ß-Cell Function After Gastric Bypass in Individuals With and Without Diabetes Remission.

OBJECTIVE: The role of the gut in diabetes remission after Roux-en-Y gastric bypass (RYGB) is incompletely understood. We assessed the temporal change in insulin secretory capacity after RYGB, using oral and intravenous (IV) glucose, in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: Longitudinal, prospective measures of ß-cell function were assessed after oral glucose intake and graded glucose infusion in individuals with severe obesity and diabetes studied at 0, 3 (n = 29), 12 (n = 24), and 24 (n = 20) months after RYGB. Data were collected between 2015 and 2019 in an academic clinical research center. RESULTS: The decreases in body weight, fat mass, waist circumference, and insulin resistance after surgery (all P < 0.001 at 12 and 24 months) did not differ according to diabetes remission status. In contrast, both the magnitude and temporal changes in ß-cell glucose sensitivity after oral glucose intake differed by remission status (P = 0.04): greater (6.5-fold; P < 0.01) and sustained in those in full remission, moderate and not sustained past 12 months in those with partial remission (3.3-fold; P < 0.001), and minimal in those not experiencing remission (2.7-fold; P = not significant). The improvement in ß-cell function after IV glucose administration was not apparent until 12 months, significant only in those in full remission, and only ∼33% of that observed after oral glucose intake. Preintervention ß-cell function and its change after surgery predicted remission; weight loss and insulin sensitivity did not. CONCLUSIONS: Our data show the time course of changes in ß-cell function after RYGB. The improvement in ß-cell function after RYGB, but not changes in weight loss or insulin sensitivity, drives diabetes remission.

Deep Neural Network-Based Survival Analysis for Skin Cancer Prediction in Heart Transplant Recipients.

Heart-transplant recipients are at high risk of developing skin cancer, while Squamous Cell Carcinoma (SCC) and Basal Cell Carcinoma (BCC) are commonly detected. This paper utilized the database from the United Network for Organ Sharing (UNOS) to study the incidence rate of SCC and BCC among heart transplant recipients. Cox proportional hazards model and two deep neural network-based models were studied, and their performance were compared. In addition, Lasso regression, Chi-square test, and Wilcoxon signed-rank test were applied to identify key risk factors. The neural network-based survival models showed better accuracy compared to the standard Cox regression model, which indicates the advantage of deep learning approaches in survival analysis and risk prediction for post-transplant skin cancer.This study investigates the performance of deep learning (DL) models in clinical applications for predicting the risk of skin cancer in heart transplant recipients. The DL models outperform the standard models in assessing the incidence rate of skin cancer across different time spans.

Risk Prediction Model for Basal Cell Carcinoma in Cardiac Allograft Recipients.

BACKGROUND: Basal cell carcinoma (BCC) is the second most common skin cancers in posttransplant patients. Long-term immunosuppression predisposes the patients to higher risk. This study was undertaken to develop a risk prediction model using the United Network for Organ Sharing (UNOS) database. MATERIALS AND METHODS: Heart transplant recipients (2000~2015) from the UNOS database were analyzed. The Cox proportional hazards model was applied to screen the predictors associated with the development of BCC. Stepwise forward selection with Akaike information criterion was done to obtain the multivariate model. Area under the curve was derived from the receiver operating characteristics curve to assess the quality of the prediction model. A risk scoring system was developed to stratify patients into different risk groups, and the occurrence rates of posttransplant BCC among different groups were compared. RESULTS: There were 24,374 patients who received heart transplantation within this study period, and 1211 recipients have been reported with BCC. The multivariate model provides area under the curves at 5, 8, and 10 years posttransplant of 0.77, 0.76, and 0.76, respectively, in the derivation set and 0.75, 0.74, and 0.74, respectively, in the validation set. The predicted and observed probabilities of developing BCC in 5 years agree well across different risk groups. Kaplan-Meier survival curves were generated, which demonstrate significant differences between subjects in different risk groups. CONCLUSION: A risk prediction model has been generated for the first time for BCC with a c-statistic of ≥0.74 in both derivation and validation sets, making it a good tool for risk stratification.

Risk prediction model for cutaneous squamous cell carcinoma in adult cardiac allograft recipients.

BACKGROUND: Heart transplant recipients are at higher risk of developing skin cancer than the general population due to the long-term immunosuppression treatment. Cancer has been reported as one of the major causes of morbidity and mortality for patients after heart transplantation. Among different types of skin cancers, cutaneous squamous cell carcinoma (cSCC) is the most common one, which requires timely screening and better management. AIM: To identify risk factors and predict the incidence of cSCC for heart transplant recipients. METHODS: We retrospectively analyzed adult heart transplant recipients between 2000 and 2015 extracted from the United Network for Organ Sharing registry. The whole dataset was randomly divided into a derivation set (80%) and a validation set (20%). Uni- and multivariate Cox regression were done to identify significant risk factors associated with the development of cSCC. Receiver operating charac-teristics curves were generated and area under the curve (AUC) was calculated to assess the accuracy of the prediction model. Based on the selected risk factors, a risk scoring system was developed to stratify patients into different risk groups. A cumulative cSCC-free survival curve was generated using the Kaplan-Meier method for each group, and the log-rank test was done to compare the inter-group cSCC rates. RESULTS: There were 23736 heart-transplant recipients during the study period, and 1827 of them have been reported with cSCC. Significant predictors of post-transplant cSCC were older age, male sex, white race, recipient and donor human leukocyte antigen (HLA) mismatch level, malignancy at listing, diagnosis with restrictive myopathy or hypertrophic myopathy, heart re-transplant, and induction therapy with OKT3 or daclizumab. The multivariate model was used to predict the 5-, 8- and 10-year incidence of cSCC and respectively provided AUC of 0.79, 0.78 and 0.77 in the derivation set and 0.80, 0.78 and 0.77 in the validation set. The risk scoring system assigned each patient with a risk score within the range of 0-11, based on which they were stratified into 4 different risk groups. The predicted and observed 5-year probability of developing cSCC match well among different risk groups. In addition, the log-rank test indicated significantly different cSCC-free survival across different groups. CONCLUSION: A risk prediction model for cSCC among heart-transplant recipients has been generated for the first time. It offers a c-statistic of ≥ 0.77 in both derivation and validation sets.

The influence of individual and neighborhood-level characteristics on rural-urban disparities in cardiovascular disease mortality among U.S. women diagnosed with breast and gynecologic cancers.

OBJECTIVE: Rural-urban disparities exist in cancer and cardiovascular disease (CVD) mortality. Investigations of CVD mortality among breast and gynecologic cancer (BGC) survivors from rural/urban communities are limited. We evaluated the influence of individual and neighborhood-level factors on rural-urban disparities in CVD mortality among BGC survivors. METHODS: Data were from 1,139,767 women aged ≥20 years from the Surveillance, Epidemiology, and End Results program who were diagnosed with BGC from 2000 to 2016 that was merged with Area Health Resource Files for neighborhood-level factors (smoking, cancer screening, primary care provider density and socioeconomic index). Standardized mortality ratios (SMRs) for CVD mortality were calculated and multilevel Cox models, accounting for competing events, were used to estimate hazards ratios (HR) and 95% confidence intervals (CI). RESULTS: The average age of BGC survivors was 60 years, with 10.3% of them living in rural counties. During a median follow-up of 5.1 years, 47,995 CVD deaths occured. Women with BGC had excess CVD mortality compared to general population women (SMR 6.05; CI: 6.00-6.11). This risk was highest among women aged <50 years (SMR = 27.16; CI: 25.74-28.62). In models adjusted for demographics, cancer stage and cancer therapy, women with BGC in rural communities had higher CVD deaths than those in urban communities (HR = 1.10, CI:1. 05-1.15). Additional adjustment for neighborhood-level characteristics attenuated the relation of rurality with CVD mortality (HR = 1.02, CI: 0.98-1.07). CONCLUSIONS: BGC survivors living in rural communities have elevated risk of CVD mortality. Neighborhood-level characteristics explained the rural-urban disparities in CVD mortality observed among BGC survivors.

Angiotensin II antagonists and gastrointestinal bleeding in left ventricular assist devices: A systematic review and meta-analysis.

Gastrointestinal bleeding (GIB) especially from arteriovenous malformations (AVM) remains one of the devastating complications following continuous-flow left ventricular device (CF-LVAD) implantation. Blockade of angiotensin II pathway using angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) was reported to mitigate the risk of GIB and AVM-related GIB by suppressing angiogenesis. We performed a systematic review and meta-analysis to evaluate the association between ACEI/ARB treatment and GIB in CF-LVAD population. Comprehensive literature search was performed through December 2019. We included studies reporting risk of GIB and/or AVM-related GIB events in LVAD patients who received ACEI/ARB with those who did not. Data from each study were combined using the random-effects to calculate odd ratios and 95% confidence intervals. Three retrospective cohort studies were included in this meta-analysis involving 619 LVADs patients (467 patients receiving ACEI/ARB). The use of ACEI/ARB was statistically associated with decreased incidence of overall GIB (pooled OR 0.35, 95% CI 0.22-0.56, I2 = 0.0%, p < 0.001). There was a non-significant trend toward lower risk for AVM-related GIB in patients who received ACEI/ARB (pooled OR 0.46, 95% CI 0.19-1.07, I2 = 51%, p = 0.07). Larger studies with specific definitions of ACEI/ARB use and GIB are warranted to accurately determine the potential non-hemodynamic benefits of ACEI/ARB in CF-LVAD patients.

Effect of Teriparatide on Bone Remodeling and Density in Premenopausal Idiopathic Osteoporosis: A Phase II Trial.

CONTEXT: Premenopausal women with idiopathic osteoporosis (IOP) have abnormal skeletal microarchitecture and variable tissue-level bone formation rate (BFR). OBJECTIVES: Compare 6 months (M) of teriparatide versus placebo on areal bone mineral density (aBMD) by dual-energy x-ray absorptiometry (DXA), bone turnover markers (BTMs) and BFR at 3M by quadruple-labeled transiliac biopsy. Characterize 12M and 24M effects of teriparatide on aBMD and whether BTMs and BFR predict response. DESIGN: 6M phase 2 randomized controlled trial (RCT) followed by open extension. SETTING: Tertiary referral centers. PATIENTS: Premenopausal women with IOP. INTERVENTIONS: A total of 41 women were randomized to either teriparatide 20 mcg (n = 28) or placebo (n = 13). After 6M, those on placebo switched to teriparatide for 24M; those on teriparatide continued for 18M. MAIN OUTCOME MEASURES: 6M RCT: Between-group differences in lumbar spine (LS) aBMD (percent change from baseline), 3M BFR, and hypercalcemia. Open-label extension: Within-group change in LS aBMD over 12M and 24M. Secondary outcomes included aBMD change at other sites and relationship between BTMs, BFR, and changes in aBMD. FINDINGS: Over 6M, LS aBMD increased by 5.5% (95% CI: 3.83, 7.19) in teriparatide and 1.5% (95% CI: -0.73, 3.83) in placebo (P = 0.007). There were increases in 3M BTMs, and BFR (cancellous and endocortical BFR: between-groups P = 0.004). Over 24M, teriparatide increased LS aBMD by 13.2% (95% CI: 10.3, 16.2), total hip by 5.2% (95% CI: 3.7, 6.7) and femoral neck by 5.0% (95% CI: 3.2, 6.7; all P ≤ 0.001). Serum N-terminal propeptides of procollagen type 1 (P1NP) and 3M endocortical BFR were moderately associated with LS aBMD response. Teriparatide was well-tolerated. CONCLUSIONS: Teriparatide increased BFR and formation markers and was associated with marked aBMD improvements in most premenopausal women (82%) with IOP.

Giant Left Ventricular Thrombus Formation in the Setting of Severe Aortic Stenosis and Heavy Cigarette Smoking.

The harmful effects of cigarette smoking on the human body have been well documented. However, whether tobacco use is an independent risk factor of valvular heart disease remains debatable. Cigarette smoking has been associated with an inflammatory state and increased levels of tumor necrosis factor alpha, which in turn activates protein kinases involved in ventricular remodeling. Subsequent ventricular dysfunction predisposes to the formation of mural thrombi which may lead to further worsening of hemodynamics. We present a case of severe aortic stenosis and giant left ventricular thrombus formation associated with chronic cigarette smoking.

Recurrent short-to-shield phenomenon requiring LVAD exchange: a rare complication.

Left ventricular assist device (LVAD) therapy is a common alternative approach for a patient with end-stage heart failure with HeartMate II (HM II) being one of the most common LVAD implants. The short-to-shield (STS) phenomenon is an uncommon drive-line (DL) dysfunction resulted from broken insulator causing an underlying wire to contact a metallic shield in a DL. This leads to a short circuit and a pump stoppage. We reported a case of 66-year-old man status post-implantation of HM II who presented with STS phenomenon. A tear at the distal end of the DL was found, and the patient underwent replacement of the extracorporeal part of DL twice. After the second repair, the pump functioned normally when tested in the hospital but the STS occurred again at home. The patient then underwent LVAD replacement surgery and insulation breach was found at one of the wires in intracorporeal part of the DL. After the surgery, the patient sustained recurrent episodes of STS and had to undergo a third extracorporeal DL repair surgery. Analysis of the removed DL confirmed an insulation breach. The STS has been resolved since then. Our case is unique as it is very rare to sustain another episode of STS shortly after a pump exchange. It also shows that the occurrence of STS can be intermittent and the area of insulation breach can be different from the area of the visualized tear. As a result, closed monitoring after DL repair must be strictly implemented.

Stem cell therapy in heart failure: Where do we stand today?

Heart failure is a global epidemic that drastically cuts short longevity and compromises quality of life. Approximately 6 million Americans ≥20 years of age carry a diagnosis of heart failure. Worldwide, about 40 million adults are affected. The treatment of HF depends on the etiology. If left untreated it rapidly progresses and compromises quality of life. One of the newer technologies still in its infancy is stem cell therapy for heart failure. This review attempts to highlight the clinical studies done in ischemic cardiomyopathy, dilated cardiomyopathy and restrictive cardiomyopathy. A combined approach of simultaneous revascularization and stem cell therapy appears to produce maximum benefit in ischemic cardiomyopathy. Treatment of dilated cardiomyopathy with stem cells also holds promise but needs more definition with regards to timing, route of cell delivery and type of cell used to achieve reproducible results. The variability noted in response to stem cell therapy in patients could also be secondary to their co-morbidities. Abnormalities of glucose metabolism and diabetes in particular impair stem cell and angiogenic cell mobilization. This opens up a whole new area of investigation into exploring the biochemical microenvironment which could influence the efficacy of stem cell therapy. This article is part of a Special Issue entitled: Stem Cells and Their Applications to Human Diseases edited by Hemachandra Reddy.

Correlations of GDF-15 with sST2, MMPs, and worsening functional capacity in idiopathic dilated cardiomyopathy: Can we gain new insights into the pathophysiology?

Growth and differentiation factor-15 (GDF-15) has been implicated in fibrosis, inflammation, and ventricular remodeling. The role of GDF-15 in the regulation of cardiac remodeling in idiopathic dilated cardiomyopathy (DCM) remains poorly defined. This study attempts to analyze the molecular interactions between GDF-15 and markers of fibrosis as well as its positive correlations with worsening functional capacity. The study population consisted of 24 DCM patients and 8 control subjects. All DCM patients had normal coronary angiographic studies. Plasma levels of GDF-15, matrix metalloproteinase-2 (MMP2), MMP3, MMP9, tissue inhibitor of MMP 1 (TIMP1), and soluble suppression of tumorigenicity-2 protein (sST2) were determined by enzyme-linked immunosorbent assays. Brain Natriuretic Peptide (BNP) was measured as per core laboratory protocol assay at Scott and White Memorial Hospital core laboratory. Correlation analysis was performed between GDF-15 and each of the MMPs-MMP2, MMP3, MMP9, and TIMP as well as New York Heart Association (NYHA) class and echocardiographic parameters (left ventricular ejection fraction (LVEF) and left ventricular internal dimension in diastole (LVIDd)). LVEF and LVIDd were obtained by two-dimensional echocardiography. The protocol was approved by Scott and White Memorial Hospital Institutional Review Board (S&W IRB). Correlation analysis of control versus all DCM patients showed a strong correlation of GDF-15 with TIMP1 (r = 0.83, p < 0.0001) and weaker correlation with MMP3 (r = 0.41, p = 0.011) and MMP2 (r = 0.47, p = 0.003). MMP9 showed poor correlation with GDF-15 (r = 0.3036, p = 0.046). GDF-15 correlated negatively with MMP2/TIMP1 ratio (r = -0.47, p = 0.006). sST2 correlated strongly with GDF-15 (r = 0.7, p < 0.0001). GDF-15 correlated negatively with LVEF (r = -0.49, p = 0.004) and positively with LVIDd (r = 0.58, p = 0.0006). GDF-15 showed significant positive correlation with NYHA functional class (r = 0.71, p < 0.00001) and BNP (r = 0.86, p < 0.00001). Significant associations of GDF-15 with MMPs, sST2, LVIDd, LVEF, and NYHA class reported here for the first time in nonischemic dilated hearts may open up new avenues of investigations to better understand molecular mechanisms controlling cardiac remodeling. This study is limited by its small size and needs validation in larger populations.

5- or/and 20-O-alkyl-2,3-dehydrosilybins: Synthesis and biological profiles on prostate cancer cell models.

To investigate the effects of alkylation at 5-OH and 20-OH of 2,3-dehydrosilybin on prostate cancer cell proliferation, the synthetic approaches to 5- or/and 20-O-alkyl-2,3-dehydrosilybins, through a multi-step sequence from commercially available silybin, have been successfully developed. The first three reactions in the syntheses were completed through a one-pot procedure by managing anaerobic and aerobic conditions. With these synthetic methods in hand, twenty-one 2,3-dehydrosilybins, including seven 20-O-alkyl, seven 5,20-O-dialkyl, and seven 5-O-alkyl-2,3-dehydrosilybins, have been achieved for the evaluation of their biological profiles. Our WST-1 cell proliferation assay data indicate that nineteen out of the twenty-one 2,3-dehydrosilybins possess significantly improved antiproliferative potency as compared with silybin toward both androgen-sensitive (LNCaP) and androgen-insensitive prostate cancer cell lines (PC-3 and DU145). 5-O-Alkyl-2,3-dehydrosilybins were identified as the optimal subgroup that can consistently inhibit cell proliferation in three prostate cancer cell models with all IC50 values lower than 8µM. Our flow cytometry-based assays also demonstrate that 5-O-heptyl-2,3-dehydrosilybin effectively arrests the cell cycle in the G0/G1 phase and activates PC-3 cell apoptosis.

Heart failure in chemotherapy-related cardiomyopathy: Can exercise make a difference?

Medical therapies in oncology have resulted in better survival resulting in a large population who are at risk of early and late cardiac complications of chemotherapy. Cardiotoxicity related to chemotherapy can manifest decades after treatment with a threefold higher mortality rate as compared to idiopathic dilated cardiomyopathy. The leading cause of death in cancer survivors seems to be cardiac. Early detection and intervention could prevent progression of heart failure to end stage disease requiring advanced therapies such as implantation of ventricular assist devices or cardiac transplantation. This review focuses on the role of exercise in cardioprotection in this population. The current practice of depending on ejection fraction for diagnosis of heart failure is suboptimal to detect subclinical disease. It is also important to diagnose and treat early diastolic dysfunction as this tends to lead to heart failure with preserved ejection fraction. Hence we suggest an algorithm here that is based on using strain rate and tissue Doppler imaging modalities to detect subclinical systolic and diastolic dysfunction. Further research is warranted in terms of defining exercise prescriptions in this population. Human studies with multicenter participation in randomized controlled trials should be done to elucidate the intricacies of aerobic exercise intervention in cardiotoxicity dependent heart failure. It is also necessary to assess the utility of exercise interventions in the different chemotherapeutic regimens as they impact the outcomes.

Particulate matter granulomas masquerading as sarcoidosis: a diagnostic dilemma.

Sarcoidosis is a multiorgan disease with no single etiology. Evidence over the years points to complex interactions between environmental and genetic factors and a hypersensitive immune response to these insults. This brief overview discusses the uncertainty in the diagnosis of sarcoidosis versus other granulomatous diseases masquerading as sarcoidosis. The diagnostic dilemma is highlighted by a brief case review. The development of newer techniques in molecular biology and the identification of a panel of biomarkers in the future with appreciable specificity and sensitivity would help in the process. Future studies to determine receiver operating curves (ROC) using multiple biomarker combinations would help develop robust testing. More in-depth studies are also needed for defining the immunological basis of sarcoidosis because recent studies implicate Th17 cells in addition to the Th1 cell pathway. It is very likely that direct exposure to environmental agents and systemic distribution of these agents can elicit an exaggerated immune response leading to multiorgan granuloma formation mimicking sarcoidosis. A genetically susceptible host may be necessary to complete the granulomatous response to the particulate matter.

Long-term immunosuppression and malignancy in thoracic transplantation: where is the balance?

Cancers in post-transplant patients exhibit the same molecular and cellular properties as those in their non-transplanted counterparts and arise secondary to uncontrolled/sustained growth, apoptosis resistance, inhibition of tumor suppressors, immortalization of cells with invasion, and and metastasis. Disruption of DNA repair mechanisms, upregulation of angiogenic growth factors, impaired viral immunity and activated oncogenic viruses contribute to the initiation of malignancies in this population. This article extends and addresses the concerns in this area. We propose potential cancer prevention strategies and a possible 4-pronged approach to prevent and treat malignancies in the post-transplant population. Future research should define strategies for immune modulation, immune suppression and malignancy prevention, including methods for naive B-cell repopulation, memory B-cell reduction and biomarker identification and utilization for predicting tolerance. Non-immune therapies, such as adjunct preventive methods and goals to modify risk factors, may reduce incidence of malignancies and pave the way to better outcomes. The role of statins is of particular interest in this context due to their pleiotropic effects on the cell cycle and their most direct role in inhibition of cholesterol biosynthesis.