Expression of IGF/insulin receptor in prostate cancer tissue and progression to lethal disease.

Circulating insulin-like growth factor-1 (IGF-1) is consistently associated with prostate cancer risk. IGF-1 binds to IGF-1 receptor (IGF1R) and insulin receptor (IR), activating cancer hallmark pathways. Experimental evidence suggests that TMPRSS2:ERG may interact with IGF/insulin signaling to influence progression. We investigated IGF1R and IR expression and its association with lethal prostate cancer among 769 men. Protein expression of IGF1R, IR and ERG (i.e. a surrogate of ERG fusion genes) were assayed by immunohistochemistry. Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI) adjusted for clinical characteristics. Among patients, 29% had strong tumor IGF1R expression and 10% had strong IR expression. During a mean follow-up of 13.2 years through 2012, 80 men (11%) developed lethal disease. Tumors with strong IGF1R or IR expression showed increased cell proliferation, decreased apoptosis and a higher prevalence of ERG. In multivariable models, strong IGF1R was associated with a borderline increased risk of lethal prostate cancer (HR 1.7; 95% CI 0.9-3.1). The association appeared greater in ERG-positive tumors (HR 2.8; 95% CI 0.9-8.4) than in ERG-negative tumors (HR 1.3; 95% CI 0.6-3.0, p-heterogeneity 0.08). There was no association between IR and lethal prostate cancer (HR 0.8; 95% CI 0.4-1.9). These results suggest that tumor IGF1R expression may play a role in prostate cancer progression to a lethal phenotype and that ERG-positive tumors may be more sensitive to IGF signaling. These data may improve our understanding of IGF signaling in prostate cancer and suggest therapeutic options for disease subtypes.

Circulating Antioxidant Levels and Risk of Prostate Cancer by TMPRSS2:ERG.

BACKGROUND: Few studies have considered etiological differences across molecular subtypes of prostate cancer, despite potential to improve opportunities for precision prevention of a disease for which modifiable risk factors have remained elusive. Factors that lead to DNA double-strand breaks, such as oxidative stress, may promote the formation of the TMPRSS2:ERG gene fusion in prostate cancer. We tested the hypothesis that increasing levels of pre-diagnostic circulating antioxidants, which may reduce oxidative stress, are associated with lower risk of developing TMPRSS2:ERG positive prostate cancer. METHODS: We conducted a nested case-control study, including 370 cases and 2,470 controls, to evaluate associations between pre-diagnostic α- and ß-carotene, α- and γ-tocopherol, ß-cryptoxanthin, lutein, lycopene, retinol, and selenium with the risk of prostate cancer by ERG protein expression status (a marker of TMPRSS2:ERG). Multivariable unconditional polytomous logistic regression was used to calculate odds ratios and 95% confidence intervals. RESULTS: We did not find any of the antioxidants to be significantly associated with the risk of prostate cancer according to ERG status. CONCLUSIONS: The results do not support the hypothesis that circulating pre-diagnostic antioxidant levels protect against developing TMPRSS2:ERG positive prostate cancer. Additional studies are needed to explore mechanisms for the development of TMPRSS2:ERG positive disease. Prostate 77: 647-653, 2017. © 2017 Wiley Periodicals, Inc.

The Association of Five-Year Changes in the Levels of N-Terminal Fragment of the Prohormone Brain-Type Natriuretic Peptide (NT-proBNP) with Subsequent Heart Failure and Death in Patients with Stable Coronary Artery Disease: The Heart and Soul Study.

BACKGROUND: The N-terminal fragment of the prohormone brain-type natriuretic peptide (NT-proBNP) is a powerful predictor of adverse outcomes in patients with coronary artery disease (CAD). However, little is known regarding the prognostic significance of longitudinal changes in NT-proBNP levels. METHODS: We evaluated the ability of 5-year changes in NT-proBNP levels to predict subsequent heart failure (HF) hospitalization or cardiovascular (CV) death in 635 participants with stable CAD enrolled in the Heart and Soul Study. RESULTS: The median (IQR) 5-year change in NT-proBNP was 50 pg/mL (-5 to +222). During an average of 4.0 ± 1.4 years follow-up (i.e., 9 years from the baseline measurement), there were 67 events. Participants with 5-year changes in the highest quartile (≥ 223 pg/mL increase in NT-proBNP) had an almost 4-fold greater risk of subsequent HF or CV death than those in the lowest quartile of ≤-5 pg/mL (HR 3.8; 95% CI 2.0-7.3; p < 0.001). This association remained strong after adjustment for demographic variables, comorbidities, left ventricular mass index, systolic and diastolic function, and baseline and follow-up NT-proBNP levels (HR 3.9; 95% CI 1.1-13.4; p = 0.01). CONCLUSION: Changes in NT-proBNP levels at 5 years predict subsequent HF or CV death in patients with stable CAD, independent of other prognostic markers, including baseline and follow-up NT-proBNP levels. A stable NT-proBNP level predicts a low risk of subsequent events.

Valves, Vegetations, and Valves.

We present a novel method for the treatment of right-sided bioprosthetic valve endocarditis with AngioVac debulking followed by percutaneous pulmonic and tricuspid valve replacement for residual transcatheter valve degeneration and right ventricular dysfunction.

Factors associated with remote monitoring adherence for cardiovascular implantable electronic devices.

BACKGROUND: Professional societies strongly recommend remote monitoring (RM) of all cardiac implantable electronic devices, and higher RM adherence is associated with improved patient outcomes. However, adherence with RM is suboptimal. OBJECTIVE: The purpose of this study was to better understand factors associated with RM adherence. METHODS: We linked RM data from the Veterans Affairs National Cardiac Device Surveillance Program to clinical data for patients monitored between October 25, 2018, and October 24, 2020. RM adherence was defined as the percentage of days covered by an RM transmission during the study period. Patients were classified into 3 categories: complete (100% of days covered by an RM transmission), intermediate (above median in patients with <100% adherence), and low (below median in patients with <100% adherence) adherence. We used multivariable logistic regression to examine patient, device, and facility characteristics associated with adherence. RESULTS: In 52,574 patients, average RM adherence was 71.9%. Only 30.9% (16,224) of patients had complete RM adherence. Black or African American patients had a lower odds of complete RM adherence than white patients (odds ratio 0.88; 95% confidence interval 0.82-0.94), and Hispanic or Latino patients had a lower odds of complete RM adherence (odds ratio 0.79; 95% confidence interval 0.70-0.89) than non-Hispanic or Latino patients. Dementia, depression, and posttraumatic stress disorder were associated with a lower odds of RM adherence. CONCLUSION: There are significant disparities in RM adherence by race, ethnicity, and neuropsychiatric comorbidities. These findings can inform strategies to improve health equity and ensure that all patients with cardiac implantable electronic devices receive the evidence-based clinical benefits of RM.

Implantable cardioverter-defibrillator placement among patients with left ventricular ejection fraction ≤35 % at least 40 days after acute myocardial infarction.

Background: Implantable cardioverter-defibrillators (ICDs) reduce the risk of sudden cardiac death among patients with persistently reduced (≤35 %) left ventricular ejection fraction (LVEF) at least 40 days following acute myocardial infarction (AMI). Few prior studies have used LVEF measured after the 40-day waiting period to examine primary prevention ICD placement. Methods: We sought to determine factors associated with ICD placement among patients who met LVEF criteria post-MI within a large integrated health care system in the U.S by conducting a retrospective cohort study of Veteran patients hospitalized for AMI from 2004 to 2017 who had documented LVEF ≤35 % from echocardiograms performed between 40 and 455 (90 days +1 year) days post-MI. We used multivariable logistic regression to examine factors associated with ICD placement. Results: Of 12,893 patients with LVEF ≤35 % at least 40 days post-MI, 2176 (16.9 %) received an ICD between 91- and 455-days post-MI. Younger age, fewer comorbidities, revascularization with PCI, and greater use of GDMT were associated with increased odds of receiving an ICD. However, half of patients treated with a beta-blocker, ACE inhibitor or angiotensin receptor blocker, and mineralocorticoid receptor antagonist prior to LVEF assessment did not receive an ICD. Eligible Black patients were less likely (odds ratio 0.80, 95 % confidence interval 0.69-0.92) to receive an ICD than White patients. Conclusion: Many factors affect ICD placement among Veteran patients with a confirmed LVEF ≤35 % at least 40 days post-MI. Greater understanding of factors influencing ICD placement would help clinicians ensure guideline-concordant care.

Cardiovascular Implications and Therapeutic Considerations in COVID-19 Infection.

The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has profoundly impacted all fields of medicine. Infection with SARS-CoV-2 and the resulting coronavirus of 2019 (COVID-19) syndrome has multiorgan effects. The pandemic has united researchers from bench to bedside in attempts to understand the pathophysiology of the disease and define optimal treatment strategies. Cardiovascular disease is highly prevalent and a leading cause of death across gender, race, and ethnic groups. As the pandemic spreads, there is increasing concern about the cardiovascular effects of the viral infection and the interaction of infection with existing cardiovascular disease. Additionally, there are concerns about the cardiac effects of the numerous treatment agents under study. It will be essential for cardiologists to understand the interplay between underlying cardiac comorbidities, acute cardiovascular effects of COVID-19 disease, and adverse effects of new treatments. Here we describe emerging evidence of the epidemiology of SARS-CoV-2 infection and underlying cardiovascular disease, the evidence for direct myocardial injury in SARS-CoV-2 infection, the specific presentations of cardiovascular involvement by SARS-CoV-2, and the cardiac effects of emerging treatments.

Conduction System Abnormalities After Transcatheter Aortic Valve Replacement: Mechanism, Prediction, and Management.

Conduction disturbances following TAVR are a common occurrence given the proximity of the various conduction system tissues, including the AV node, His-bundle, and bundle branches to the left ventricular outflow tract and aortic root. Impairment of these conduction system abnormalities may necessitate permanent pacemaker implantation, which increases morbidity and mortality, as well as length of stay, for the patient. The incidence, mechanisms, and predictors of conduction abnormalities and treatment options are discussed in this up-to-date review of the topic.

Evolution reversed: the ability to bind iron restored to the N-lobe of the murine inhibitor of carbonic anhydrase by strategic mutagenesis.

The murine inhibitor of carbonic anhydrase (mICA) is a member of the superfamily related to the bilobal iron transport protein transferrin (TF), which binds a ferric ion within a cleft in each lobe. Although the gene encoding ICA in humans is classified as a pseudogene, an apparently functional ICA gene has been annotated in mice, rats, cows, pigs, and dogs. All ICAs lack one (or more) of the amino acid ligands in each lobe essential for high-affinity coordination of iron and the requisite synergistic anion, carbonate. The reason why ICA family members have lost the ability to bind iron is potentially related to acquiring a new function(s), one of which is inhibition of certain carbonic anhydrase (CA) isoforms. A recombinant mutant of the mICA (W124R/S188Y) was created with the goal of restoring the ligands required for both anion (Arg124) and iron (Tyr188) binding in the N-lobe. Absorption and fluorescence spectra definitively show that the mutant binds ferric iron in the N-lobe. Electrospray ionization mass spectrometry confirms the presence of both ferric iron and carbonate. At the putative endosomal pH of 5.6, iron is released by two slow processes indicative of high-affinity coordination. Induction of specific iron binding implies that (1) the structure of mICA resembles those of other TF family members and (2) the N-lobe can adopt a conformation in which the cleft closes when iron binds. Because the conformational change in the N-lobe indicated by metal binding does not impact the inhibitory activity of mICA, inhibition of CA was tentatively assigned to the C-lobe. Proof of this assignment is provided by limited trypsin proteolysis of porcine ICA.

Longitudinal Blood Pressure Changes and Kidney Function Decline in Persons Without Chronic Kidney Disease: Findings From the MESA Study.

BACKGROUND: While changes in blood pressure (BP) are independently associated with cardiovascular events, less is known about the association between changes in BP and subsequent changes in renal function in adults with an estimated glomerular filtration rate (eGFR) of >60 ml/min/1.73 m2. METHODS: The present study included 3,920 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) study who had ≥2 BP measurements during the first 5 years of MESA and had eGFR measurements at both year 5 and 10. Change in BP was estimated as the annualized slope of BP between year 0 and 5 based on linear mixed models (mean number of measurements = 4.0). Participants were then grouped into 1 of 3 categories based on the distribution of systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) change (top 20%, middle 21-79%, bottom 20%). We calculated eGFR from cystatin C (ml/min/1.73 m2), estimated annual change in eGFR (ml/min/1.73 m2/year), and defined rapid kidney function decline as a >30% decrease in eGFR from year 5 to 10. We used multivariable logistic regression adjusting for year 0 demographic and clinical characteristics, including eGFR and BP, to determine associations of BP change with rapid kidney function decline. RESULTS: Median age was 59 [interquartile range (IQR): 52, 67] and median eGFR at year 0 was 95.5 (IQR: 81.7, 105.9) ml/min/1.73 m2. Median SBP at year 0 was 111, 121, and 147 mm Hg for increasing, stable, and decreasing SBP change, respectively. Increasing SBP and widening PP change were each associated with higher odds of rapid kidney function decline compared with stable SBP and PP groups, respectively [odds ratio, OR 1.7 (95% confidence interval, CI 1.3, 2.4) for SBP; OR 1.4 (95% CI 1.1, 1.9) for PP]. Decreasing SBP was associated with rapid kidney function decline after adjusting for all covariates except for year 0 BP [OR 1.4 (95% CI 1.0, 1.8)], but this association was no longer statistically significant after adjustment for year 0 BP. There were no significant associations between DBP change and rapid decline in the fully adjusted models. Similar findings were seen with annual change in eGFR. CONCLUSIONS: Increasing SBP and widening PP over time were associated with greater risk for accelerated kidney function decline even at BP levels below established hypertension thresholds.

SPINK1 protein expression and prostate cancer progression.

PURPOSE: SPINK1 overexpression has been described in prostate cancer and is linked with poor prognosis in many cancers. The objective of this study was to characterize the association between SPINK1 overexpression and prostate cancer-specific survival. EXPERIMENTAL DESIGN: The study included 879 participants in the U.S. Physicians' Health Study and Health Professionals Follow-Up Study, diagnosed with prostate cancer (1983-2004) and treated by radical prostatectomy. Protein tumor expression of SPINK1 was evaluated by immunohistochemistry on tumor tissue microarrays. RESULTS: Seventy-four of 879 (8%) prostate cancer tumors were SPINK1 positive. Immunohistochemical data were available for PTEN, p-Akt, pS6, stathmin, androgen receptor (AR), and ERG (as a measure of the TMPRSS2:ERG translocation). Compared with SPINK1-negative tumors, SPINK1-positive tumors showed higher PTEN and stathmin expression, and lower expression of AR (P < 0.01). SPINK1 overexpression was seen in 47 of 427 (11%) ERG-negative samples and in 19 of 427 (4%) ERG-positive cases (P = 0.0003). We found no significant associations between SPINK1 status and Gleason grade or tumor stage. There was no association between SPINK1 expression and biochemical recurrence (P = 0.56). Moreover, there was no association between SPINK1 expression and prostate cancer mortality (there were 75 lethal cases of prostate cancer during a mean of 13.5 years follow-up; HR = 0.71; 95% confidence interval, 0.29-1.76). CONCLUSIONS: Our results suggest that SPINK1 protein expression may not be a predictor of recurrence or lethal prostate cancer amongst men treated by radical prostatectomy. SPINK1 and ERG protein expression do not seem to be entirely mutually exclusive, as some previous studies have suggested.

Immunohistochemical expression of BRCA1 and lethal prostate cancer.

BRCA1 functions as a tumor suppressor; recent work suggests that BRCA1 may also induce cell cycle arrest to allow for DNA repair. We hypothesized that BRCA1 expression in prostate tumor tissue may be associated with prostate cancer progression through regulation of the cell cycle. We used immunohistochemistry to evaluate BRCA1 protein expression in archival tumor samples from 393 prostate cancer cases in the Physicians' Health Study. The men were followed prospectively from diagnosis to development of metastases and mortality. Fifteen percent of tumors stained positive for BRCA1. BRCA1-positive tumors had substantially increased tumor proliferation index compared with negative tumors (47.0 Ki67-positive nuclei versus 10.3, P = 0.0016) and were more likely to develop lethal cancer compared with BRCA1-negative tumors (hazard ratio, 4.6; 95% confidence interval, 2.4-8.7). These findings strengthen the hypothesis that BRCA1 plays a role in cell cycle control and show that BRCA1 is a marker of clinical prostate cancer prognosis. Cancer Res; 70(8); 3136-9. (c)2010 AACR.

Prospective study of Trichomonas vaginalis infection and prostate cancer incidence and mortality: Physicians' Health Study.

BACKGROUND: A recent nested case-control study found that the presence of antibodies against Trichomonas vaginalis, a common nonviral sexually transmitted infection, was positively associated with subsequent incidence of prostate cancer. We confirmed these findings in an independent population and related serostatus for antibodies against T vaginalis to prostate cancer incidence and mortality. METHODS: We conducted a case-control study nested within the Physicians' Health Study that included 673 case subjects with prostate cancer and 673 individually matched control subjects who had available plasma samples. Plasma from blood samples collected at baseline was assayed for antibodies against T vaginalis with an enzyme-linked immunosorbent assay. We used conditional logistic regression to estimate the odds ratios (ORs) of incident prostate cancer, extraprostatic prostate cancer, and cancer that would ultimately progress to bony metastases or prostate cancer-specific death. RESULTS: Although not statistically significant, the magnitude of the association between T vaginalis-seropositive status and overall prostate cancer risk (OR = 1.23, 95% confidence interval [CI] = 0.94 to 1.61) was similar to that reported previously. Furthermore, a seropositive status was associated with statistically significantly increased risks of extraprostatic prostate cancer (OR = 2.17, 95% CI = 1.08 to 4.37) and of cancer that would ultimately progress to bony metastases or prostate cancer-specific death (OR = 2.69, 95% CI = 1.37 to 5.28). CONCLUSIONS: This large prospective case-control study obtained further support for an association between a seropositive status for antibodies against T vaginalis and the risk of prostate cancer, with statistically significant associations identified for the risk of extraprostatic prostate cancer and for clinically relevant, potentially lethal prostate cancer.