Evidence That Anemia Accelerates AS Progression Via Shear-Induced TGF-ß1 Activation: Heyde's Syndrome Comes Full Circle.

The severity of aortic stenosis (AS) is associated with acquired von Willebrand syndrome (AVWS) and gastrointestinal bleeding, leading to anemia (Heyde's syndrome). We investigated how anemia is linked with AS and AVWS using the LA100 mouse model and patients with AS. Induction of anemia in LA100 mice increased transforming growth factor (TGF)-ß1 activation, AVWS, and AS progression. Patients age >75 years with severe AS had higher plasma TGF-ß1 levels and more severe anemia than AS patients age <75 years, and there was a correlation between TGF-ß1 and anemia. These data are compatible with the hypothesis that the blood loss anemia of Heyde's syndrome contributes to AS progression via WSS-induced activation of platelet TGF-ß1 and additional gastrointestinal bleeding via WSS-induced AVWS.

Deploying a novel custom mobile application for STEMI activation and transfer in a large healthcare system to improve cross-team workflow. STEMIcathAID implementation project.

BACKGROUND: ST-segment elevation myocardial infarction (STEMI) is a high-risk patient medical emergency. We developed a secure mobile application, STEMIcathAID, to optimize care for STEMI patients by providing a digital platform for communication between the STEMI care team members, EKG transmission, cardiac catherization laboratory (cath lab) activation and ambulance tracking. The aim of this report is to describe the implementation of the app into the current STEMI workflow in preparation for a pilot project employing the app for inter-hospital STEMI transfer. APPROACH: App deployment involved key leadership stakeholders from all multidisciplinary teams taking care of STEMI patients. The team developed a transition plan addressing all aspects of the health system improvement process including the workflow analysis and redesign, app installation, personnel training including user account access to the app, and development of a quality assurance program for progress evaluation. The pilot will go live in the Emergency Department (ED) of one of the hospitals within the Mount Sinai Hospital System (MSHS) during the daytime weekday hours at the beginning and extending to 24/7 schedule over 4-6 weeks. For the duration of the pilot, ED personnel will combine the STEMIcathAID app activation with previous established STEMI activation processes through the MSHS Clinical Command Center (CCC) to ensure efficient and reliable response to a STEMI alert. More than 250 people were provisioned app accounts including ED Physicians and frontline nurses, and trained on their user-specific roles and responsibilities and scheduled in the app. The team will be provided with a feedback form that is discipline specific to complete after every STEMI case in order to collect information on user experience with the STEMIcathAID app functionality. The form will also provide quantitative metrics for the key time sensitive steps in STEMI care. CONCLUSIONS: We developed a uniform approach for deployment of a mobile application for STEMI activation and transfer in a large urban healthcare system to optimize the clinical workflow in STEMI care. The results of the pilot will demonstrate whether the app has a significant impact on the quality of care for transfer of STEMI patients.

Retrospective analysis of demographic factors in COVID-19 patients entering the Mount Sinai Health System.

With the continued rise of the global incidence of COVID-19 infection and emergent second wave, the need to understand characteristics that impact susceptibility to infection, clinical severity, and outcomes remains vital. The objective of this study was to assess modifying effects of demographic factors on COVID-19 testing status and outcomes in a large, diverse single health system cohort. The Mount Sinai Health System de-identified COVID-19 database contained records of 39,539 patients entering the health system from 02/28/2020 to 06/08/2020 with 7,032 laboratory-confirmed cases. The prevalence of qRT-PCR nasopharyngeal swabs (χ2 = 665.7, p<0.0001) and case rates (χ2 = 445.3, p<0.0001) are highest in Hispanics and Black or African Americans. The likelihood of admission and/or presentation to an intensive care unit (ICU) versus non-ICU inpatient unit, emergency department, and outpatient services, which reflects the severity of the clinical course, was also modified by race and ethnicity. Females were less likely to be tested [Relative Risk(RR) = 1.121, p<0.0001], and males had a higher case prevalence (RR = 1.224, p<0.001). Compared to other major ethnic groups, Whites experienced a higher prevalence of mortality (p<0.05). Males experienced a higher risk of mortality (RR = 1.180, p = 0.0012) at relatively younger ages (70.58±11.75) compared to females (73.02±11.46) (p = 0.0004). There was an increased severity of disease in older patient populations of both sexes. Although Hispanic and Black or African American race was associated with higher testing prevalence and positive testing rates, the only disparity with respect to mortality was a higher prevalence in Whites.

Comorbidities, sequelae, blood biomarkers and their associated clinical outcomes in the Mount Sinai Health System COVID-19 patients.

With the continuing rise of SARS-CoV2 infection globally and the emergence of various waves in different countries, understanding characteristics of susceptibility to infection, clinical severity, and outcomes remain vital. In this retrospective study, data was extracted for 39,539 patients from the de-identified Mount Sinai Health System COVID-19 database. We assessed the risk of mortality based on the presence of comorbidities and organ-specific sequelae in 7,032 CoV2 positive (+) patients. Prevalence of cardiovascular and metabolic comorbidities was high among SARS-CoV2+ individuals. Diabetes, obesity, coronary artery disease, hypertension, atrial fibrillation, and heart failure all increased overall mortality risk, while asthma did not. Ethnicity modified the risk of mortality associated with these comorbidities. With regards to secondary complications in the setting of infection, individuals with acute kidney injury and acute myocardial injury showed an increase in mortality risk. Cerebral infarcts and acute venous thromboembolic events were not associated with increased risk of mortality. Biomarkers for cardiovascular injury, coagulation, and inflammation were compared between deceased and survived individuals. We found that cardiac and coagulation biomarkers were elevated and fell beyond normal range more often in deceased patients. Several, but not all, inflammatory markers evaluated were increased in deceased patients. In summary, we identified comorbidities and sequelae along with peripheral blood biomarkers that were associated with elevated clinical severity and poor outcomes in COVID-19 patients. Overall, these findings detail the granularity of previously reported factors which may impact susceptibility, clinical severity, and mortality during the course of COVID-19 disease.

Mobile application to optimize care for ST-segment elevation myocardial infarction patients in a large healthcare system, STEMIcathAID: rationale and design.

Aims: Technological advancements have transformed healthcare. System delays in transferring patients with ST-segment elevation myocardial infarction (STEMI) to a primary percutaneous coronary intervention (PCI) centre are associated with worse clinical outcomes. Our aim was to design and develop a secure mobile application, STEMIcathAID, streamlining communication, and coordination between the STEMI care teams to reduce ischaemia time and improve patient outcomes. Methods and results: The app was designed for transfer of patients with STEMI to a cardiac catheterization laboratory (CCL) from an emergency department (ED) of either a PCI capable or a non-PCI capable hospital. When a suspected STEMI arrives to a non-PCI hospital ED, the ED physician uploads the electrocardiogram and relevant patient information. An instant notification is simultaneously sent to the on-call CCL attending and transfer centre. The attending reviews the information, makes a video call and decides to either accept or reject the transfer. If accepted, on-call CCL team members receive an immediate push notification and begin communicating with the ED team via a HIPAA compliant chat. The app provides live GPS tracking of the ambulance and frequent clinical status updates of the patient. In addition, it allows for screening of STEMI patients in cardiogenic shock. Prior to discharge, important data elements have to be entered to close the case. Conclusion: We developed a novel mobile app to optimize care for STEMI patients and facilitate electronic extraction of relevant performance metrics to improve allocation of resources and reduction of costs.

Outcomes of Impella-supported high-risk nonemergent percutaneous coronary intervention in a large single-center registry.

OBJECTIVES: We aimed to evaluate the early and one-year outcomes of Impella-supported high-risk nonemergent percutaneous coronary intervention (PCI). BACKGROUND: The evidence for the use of mechanical circulatory support (MCS) devices in high-risk nonemergent PCI is limited and nonconclusive. METHODS: We performed a single-center retrospective study including all patients who underwent high-risk nonemergent PCI supported by Impella 2.5/CP at our institution between January 2009 and June 2018. This patient population was propensity score matched with subjects undergoing PCI with no MCS. The primary endpoint was major adverse cardiac events (MACE: all-cause death, myocardial infarction [MI], and target lesion revascularization) at one-year follow-up. RESULTS: Two-hundred fifty patients undergoing Impella-supported nonemergent PCI were matched to 250 controls. The two groups were well balanced in terms of clinical and angiographic characteristics. Left main PCI was performed more frequently among Impella-supported patients (26% vs. 11%, p < .001), who also had numerically higher prevalence of rotational atherectomy use (44% vs. 37%, p = .10) and a higher number of vessels treated (1.8 ± 0.8 vs. 1.3 ± 0.6, p < .001), compared with controls. Impella-supported patients suffered a higher incidence of periprocedural MI (14.0% vs. 6.4%, p = .005), major bleeding (6.8% vs. 2.8%, p = .04), and need for blood transfusions (11.2% vs. 4.8%, p = .008). However, at one-year follow-up there were no differences in the rates of MACE (31.2% vs. 27.4%, p = .78) or any of its individual components between Impella-supported patients and controls. CONCLUSIONS: Although Impella-supported patients suffer a higher incidence of periprocedural adverse events (partially linked to more aggressive PCI), the incidence of one-year MACE was similar between the Impella and control group.

Convalescent plasma treatment of severe COVID-19: a propensity score-matched control study.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a new human disease with few effective treatments1. Convalescent plasma, donated by persons who have recovered from COVID-19, is the acellular component of blood that contains antibodies, including those that specifically recognize SARS-CoV-2. These antibodies, when transfused into patients infected with SARS-CoV-2, are thought to exert an antiviral effect, suppressing virus replication before patients have mounted their own humoral immune responses2,3. Virus-specific antibodies from recovered persons are often the first available therapy for an emerging infectious disease, a stopgap treatment while new antivirals and vaccines are being developed1,2. This retrospective, propensity score-matched case-control study assessed the effectiveness of convalescent plasma therapy in 39 patients with severe or life-threatening COVID-19 at The Mount Sinai Hospital in New York City. Oxygen requirements on day 14 after transfusion worsened in 17.9% of plasma recipients versus 28.2% of propensity score-matched controls who were hospitalized with COVID-19 (adjusted odds ratio (OR), 0.86; 95% confidence interval (CI), 0.75-0.98; chi-square test P value = 0.025). Survival also improved in plasma recipients (adjusted hazard ratio (HR), 0.34; 95% CI, 0.13-0.89; chi-square test P = 0.027). Convalescent plasma is potentially effective against COVID-19, but adequately powered, randomized controlled trials are needed.

Clinical Implications of SARS-CoV-2 Interaction With Renin Angiotensin System: JACC Review Topic of the Week.

Severe acute respiratory-syndrome coronavirus-2 (SARS-CoV-2) host cell infection is mediated by binding to angiotensin-converting enzyme 2 (ACE2). Systemic dysregulation observed in SARS-CoV was previously postulated to be due to ACE2/angiotensin 1-7 (Ang1-7)/Mas axis downregulation; increased ACE2 activity was shown to mediate disease protection. Because angiotensin II receptor blockers, ACE inhibitors, and mineralocorticoid receptor antagonists increase ACE2 receptor expression, it has been tacitly believed that the use of these agents may facilitate viral disease; thus, they should not be used in high-risk patients with cardiovascular disease. Based on the anti-inflammatory benefits of the upregulation of the ACE2/Ang1-7/Mas axis and previously demonstrated benefits of lung function improvement in SARS-CoV infections, it has been hypothesized that the benefits of treatment with renin-angiotensin system inhibitors in SARS-CoV-2 may outweigh the risks and at the very least should not be withheld.

New methodologies to accurately assess circulating active transforming growth factor-ß1 levels: implications for evaluating heart failure and the impact of left ventricular assist devices.

Transforming growth factor-ß1 (TGF-ß1) has been used as a biomarker in disorders associated with pathologic fibrosis. However, plasma TGF-ß1 assessment is confounded by the significant variation in reported normal values, likely reflecting variable release of the large pool of platelet TGF-ß1 after blood drawing. Moreover, current assays measure only total TGF-ß1, which is dominated by the latent form of TGF-ß1 rather than the biologically active form. To address these challenges, we developed methodologies to prevent ex vivo release of TGF-ß1 and to quantify active TGF-ß1. We then used these techniques to measure TGF-ß1 in healthy controls and patients with heart failure (HF) before and after insertion of left ventricular assist devices (LVAD). Total plasma TGF-ß1 was 1.0 ± 0.60 ng/mL in controls and 3.76 ± 1.55 ng/mL in subjects with HF (P < 0.001), rising to 5.2 ± 2.3 ng/mL following LVAD placement (P = 0.006). These results were paralleled by the active TGF-ß1 values; controls had 3-16 pg/mL active TGF-ß1, whereas levels were 2.7-fold higher in patients with HF before, and 4.2-fold higher after, LVAD implantation. Total TGF-ß1 correlated with levels of the platelet-derived protein thrombospondin-1 (r = 0.87; P < 0.001), suggesting that plasma TGF-ß1 may serve as a surrogate indicator of in vivo platelet activation. von Willebrand factor high molecular weight multimers correlated inversely with TGF-ß1 levels (r = -0.63; P = 0.023), suggesting a role for shear forces in loss of these multimers and platelet activation. In conclusion, accurate assessment of circulating TGF-ß1 may provide a valuable biomarker for in vivo platelet activation and thrombotic disorders.

Renal cell carcinoma with inferior vena cava thrombus extending to the right atrium diagnosed during pregnancy.

Only one case of renal cell carcinoma (RCC) with inferior vena cava (IVC) tumor thrombus diagnosed and treated during pregnancy has been reported in the literature. In that report, the tumor thrombus extended to the infrahepatic IVC (level II tumor thrombus). In the present case, a 37-year-old woman with lupus anticoagulant antibodies was diagnosed with RCC and IVC tumor thrombus extending to the right atrium (level IV tumor thrombus) at 24 weeks of pregnancy. The fetus was safely delivered by cesarean section at 30 weeks of gestation. At 4 days later, an open right radical nephrectomy and IVC and right atrial thrombectomy were performed on cardiopulmonary bypass (CPB) once the patient's hemodynamic status had been optimized. Fetal and maternal concerns included the risk of a thromboembolic event (due to increased hypercoagulability from pregnancy, active malignancy, and lupus anticoagulant), intraoperative hemorrhage risk (due to extensive venous collaterals and anticoagulation), and fetal morbidity and mortality (due to fetal lung immaturity). Standardized guidelines for treatment of RCC with or without IVC tumor thrombus during pregnancy are unavailable due to the infrequency of such cases. Treatment decisions are therefore individualized and this case report may inform the management of future patients diagnosed with RCC with level IV tumor thrombus during pregnancy.

An allele-specific PCR system for rapid detection and discrimination of the CYP2C19∗4A, ∗4B, and ∗17 alleles: implications for clopidogrel response testing.

CYP2C19 is involved in the metabolism of clinically relevant drugs, including the antiplatelet prodrug clopidogrel, which has prompted interest in clinical CYP2C19 genotyping. The CYP2C19∗4B allele is defined by both gain-of-function [c.-806C>T (∗17)] and loss-of-function [c.1A>G (∗4)] variants on the same haplotype; however, current genotyping and sequencing assays are unable to determine the phase of these variants. Thus, the aim of this study was to develop an assay that could rapidly detect and discriminate the related ∗4A, ∗4B, and ∗17 alleles. An allele-specific PCR assay, composed of four unique primer mixes that specifically interrogate the defining ∗17 and ∗4 variants, was developed by using samples (n = 20) with known genotypes, including the ∗4A, ∗4B, and/or ∗17 alleles. The assay was validated by testing 135 blinded samples, and the results were correlated with CYP2C19 genotyping and allele-specific cloning/sequencing. Importantly, among the six ∗4 carriers in the validation cohort, after allele-specific PCR testing both samples with a ∗1/∗4 genotype were reclassified to ∗1/∗4A, all three samples with a ∗4/∗17 genotype were reclassified to ∗1/∗4B, and a sample with a ∗4/∗17/∗17 genotype was reclassified to ∗4B/∗17. In conclusion, this rapid and robust allele-specific PCR assay can refine CYP2C19 genotyping and metabolizer phenotype classification by determining the phase of the defining ∗17 and ∗4 variants, which may have utility when testing CYP2C19 for clopidogrel response.

Combined and independent impact of diabetes mellitus and chronic kidney disease on residual platelet reactivity.

Patients with both chronic kidney disease (CKD) and diabetes mellitus (DM) are at increased risk for thrombotic events compared to those with one abnormality alone. Whether this can be attributed to changes in platelet reactivity among those with both CKD and DM is unknown. We prospectively studied 438 clopidogrel-naïve patients undergoing percutaneous coronary intervention (PCI). Platelet function tests were performed 4-6 hours after loading with 600 mg of clopidogrel. Platelet reactivity was assessed using the VerifyNow system and expressed as P2Y12 reaction units (PRU). High residual platelet reactivity (HRPR) was defined as PRU > 230. Patients were categorised into four groups by the presence or absence of CKD and DM. Among those without CKD or DM (n=166), DM alone (n=150), CKD alone (n=60) and both CKD and DM (n=62) the mean PRU levels were 201.6 ± 96.3, 220.5 ± 101.1, 254.9 ± 106.7 and 275.0 ± 94.5, respectively (p<0.001). Analogously, the prevalence of HRPR was 42.3%, 50.7%, 63.3% and 75.8%, respectively (p< 0.001). Associations between either CKD or DM alone and HRPR were attenuated after multivariable adjustment while the odds for HRPR associated with both CKD and DM remained significant (OR [95% CI]: 2.61 [1.16 - 5.86]). In conclusion, the presence of both CKD and DM confers a synergistic impact on residual platelet reactivity when compared to either condition alone. Whether more potent platelet inhibitors may improve outcomes among patients with both abnormalities warrants investigation.

Changes in von Willebrand factor-cleaving protease (ADAMTS-13) in patients with aortic stenosis undergoing valve replacement or balloon valvuloplasty.

It was the objective of this study to determine whether reduced cleavage of von Willebrand factor (VWF) multimers following aortic valve replacement (AVR) is a consequence of reduced shear stress or postoperative changes in VWF cleavage protease (ADAMTS-13) activity. Aortic stenosis (AS) may be complicated by acquired von Willebrand disease. Aortic valve replacement (AVR) corrects the associated haematologic abnormalities. We enrolled 114 patients with severe AS scheduled for either balloon aortic valvuloplasty (BAV; n=64) or AVR (n=50). Haematologic assessments of VWF levels and activity and ADAMTS-13 were performed before and 24 hours after valve intervention. The VWF:RCo to VWF:Ag ratio, a surrogate for large VWF multimer activity, increased by 37% (p < 0.0001) after AVR and by 10% (p = 0.0002) after BAV. ADAMTS-13 activity significantly decreased after AVR (579 ± 127 to 468 ± 135 ng/ml; p<0.0001), but not after BAV (484 ± 153 to 529 ± 185 ng/ml; p = 0.10). By multivariable analysis, the change in VWF:RCo ratio after AVR was more strongly associated with the fall in ADAMTS-13 than with reduction of valve gradient; whereas the change in gradient better predicted the rise in VWF:RCo after BAV. In conclusion, both BAV and AVR reverse the haematological abnormalities of the acquired von Willebrand syndrome of AS and ADAMTS-13 levels decrease after AVR. These findings suggest that a portion of the haematologic benefit of AVR may be due to a postoperative decline in ADAMTS-13 rather than solely to relief of AS as previously thought.