Faculty Bibliography
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MAGNETIC RESONANCE IMAGING EVALUATION OF MINERALOCORTICOID RECEPTOR ANTAGONISM IN DIABETIC ATHEROSCLEROSIS (MAGMA): [Meeting Abstract]
Pharmacological studies and clinical trials have validated the use of mineralocorticoid receptor (MR) antagonists in the management of patients with diabetic chronic kidney disease (CKD), however the mechanisms of action are not fully understood. Persistent MR activation may represent a common pathway for inflammation and atherosclerosis in type II diabetes (T2D) and CKD. MAGMA was a randomized, double-blind, placebo controlled, proof-of-conc pt trial comparing the effects of Spironolactone 25 mg/day vs. placebo in patients with CKD stages 3-4, T2D, on maximal RAS blockade, and a prior atherosclerotic event and/or left ventricular (LV) hypertrophy. The primary outcome was % change in thoracic aortic wall volume at 12 months. Secondary outcomes were LV mass regression; LV fibrosis (change in native T1) and changes in proteomic profile. Seventy-nine patients were randomized at 4 sites in US and Canada to Spironolactone (n=37) vs placebo (n=42) for 12 months, after a 2-week single-blind placebo lead-in period and 4-week dose escalation phase. Mean age was 64+/-8 years; HbA1c 7.3+/-1.3%; eGFR 44 ml/min/1.73m2; baseline systolic BP 132+/-19 mmHg. TABLE provides the top results. Spironolactone halts the progression of atherosclerosis, and results in reduction in LV mass, and myocardial fibrosis in T2D patients with CKD. Proteomic changes will be presented. [Table presented]
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EMBASE:2023858069
ISSN: 1523-6838
CID: 5515512
A pilot open-label study of aldose reductase inhibition with AT-001 (caficrestat) in patients hospitalized for COVID-19 infection: Results from a registry-based matched-control analysis
BACKGROUND AND AIMS/OBJECTIVE:Cardiometabolic disease may confer increased risk of adverse outcomes in COVID-19 patients by activation of the aldose reductase pathway. We hypothesized that aldose reductase inhibition with AT-001 might reduce viral inflammation and risk of adverse outcomes in diabetic patients with COVID-19. METHODS:We conducted an open-label prospective phase 2 clinical trial to assess safety, tolerability and efficacy of AT-001 in patients hospitalized with COVID-19 infection, history of diabetes mellitus and chronic heart disease. Eligible participants were prospectively enrolled and treated with AT-001 1500Â mg BID for up to 14 days. Safety, tolerability, survival and length of hospital stay (LOS) were collected from the electronic medical record and compared with data from two matched control groups (MC1 and MC2) selected from a deidentified registry of COVID-19 patients at the same institution. RESULTS:AT-001 was safe and well tolerated in the 10 participants who received the study drug. In-hospital mortality observed in the AT-001 group was 20% vs. 31% in MC1 and 27% in MC2. Mean LOS observed in the AT-001 group was 5 days vs. 10 days in MC1 and 25 days in MC2. CONCLUSIONS:In hospitalized patients with COVID-19 and co-morbid diabetes mellitus and heart disease, treatment with AT-001 was safe and well tolerated. Exposure to AT-001 was associated with a trend of reduced mortality and shortened LOS. While the observed trend did not reach statistical significance, the present study provides the rationale for investigating potential benefit of AT-001 in COVID 19 affected patients in future studies.
PMCID:8556062
PMID: 34752935
ISSN: 1878-0334
CID: 5050382
Association of anti-phospholipid antibodies (APL) with poor clinical outcomes in hospitalized patients with COVID-19 [Meeting Abstract]
Background/Purpose: Critically ill patients with COVID-19 infection have a profound hypercoagulable state and can often develop thromboses in many different vascular beds. Given the presence of anti-phospholipid antibodies among COVID-19 patients reported previously, we hypothesized that poor outcomes and thrombosis could also be promoted by autoimmunity. In this retrospective case control analysis, we aimed to evaluate associations between aPL titers, clinical outcomes and mortality in hospitalized patients admitted with COVID-19 infection.
Method(s): We analyzed 138 electronic medical records of patients who were admitted to NYU Langone Hospital -Long Island between the months of March-April 2020 with findings of COVID-19 positivity via PCR and who had aPL titers determined. Patients with elevated titers of beta-2-Glycoprotein IgG, IgM, IgA and/or cardiolipin IgG, IgM, IgA were compared to those who were not elevated. Patients with positive lupus anticoagulant titers only were excluded due to prevalent use of anti-coagulation during this time. COVID-19 positive patients with aPL titers were assessed for clinical events (including DVT, PE, MI, CVA, extremity ischemia, skin ulcerations, visceral thrombosis and ocular and line occlusions) and mortality. The control group included patients that were negative for aPL antibody titers. Associations between Anti-Phospholipid (aPL) titer positivity and clinical events was assessed by Chi-square analysis using Fisher's exact test.
Result(s): The predominant aPL species that was noted in COVID-19 patients was anti-cardiolipin IgM. Of those patients with elevated antibody titers, cardiolipin IgM, IgG, IgA, and beta2GPI antibodies were prevalent at rates of 98.9%, 26.7%, 19.2%, and 16.5%, respectively. Multiple aPL isotypes were detected in several patients. There was a positive association between aPL positivity and elevations in IL-6, CRP, D-dimer, and LDH (P< 0.05). There was an increased incidence of clinical events in patients with COVID-19 and positive aPL titers (52/83 or 62%) compared to those who were aPL negative (32/55 or 58% ), however this association was not statistically significant. No significant association was detected between positive aPL titers and gender, age, or self-identified ethnicity. An increased incidence of ARDS and a rising serum creatinine was noted in the aPL positive group (P = 0.03 and P= 0.05 respectively). A significant increase in mortality was identified for the aPL positive group (P=0.01).
Conclusion(s): These findings suggest that aPL titers may provide insight into disease prognosis and outcome in hospitalized patients with COVID-19. Despite lack of significant association with discrete thrombotic events, association of aPL positivity with rising serum creatinine and ARDS suggest that aPL may contribute to end organ dysfunction through enhanced microthrombosis, resulting in increased mortality. (Figure Presented)
Method(s): We analyzed 138 electronic medical records of patients who were admitted to NYU Langone Hospital -Long Island between the months of March-April 2020 with findings of COVID-19 positivity via PCR and who had aPL titers determined. Patients with elevated titers of beta-2-Glycoprotein IgG, IgM, IgA and/or cardiolipin IgG, IgM, IgA were compared to those who were not elevated. Patients with positive lupus anticoagulant titers only were excluded due to prevalent use of anti-coagulation during this time. COVID-19 positive patients with aPL titers were assessed for clinical events (including DVT, PE, MI, CVA, extremity ischemia, skin ulcerations, visceral thrombosis and ocular and line occlusions) and mortality. The control group included patients that were negative for aPL antibody titers. Associations between Anti-Phospholipid (aPL) titer positivity and clinical events was assessed by Chi-square analysis using Fisher's exact test.
Result(s): The predominant aPL species that was noted in COVID-19 patients was anti-cardiolipin IgM. Of those patients with elevated antibody titers, cardiolipin IgM, IgG, IgA, and beta2GPI antibodies were prevalent at rates of 98.9%, 26.7%, 19.2%, and 16.5%, respectively. Multiple aPL isotypes were detected in several patients. There was a positive association between aPL positivity and elevations in IL-6, CRP, D-dimer, and LDH (P< 0.05). There was an increased incidence of clinical events in patients with COVID-19 and positive aPL titers (52/83 or 62%) compared to those who were aPL negative (32/55 or 58% ), however this association was not statistically significant. No significant association was detected between positive aPL titers and gender, age, or self-identified ethnicity. An increased incidence of ARDS and a rising serum creatinine was noted in the aPL positive group (P = 0.03 and P= 0.05 respectively). A significant increase in mortality was identified for the aPL positive group (P=0.01).
Conclusion(s): These findings suggest that aPL titers may provide insight into disease prognosis and outcome in hospitalized patients with COVID-19. Despite lack of significant association with discrete thrombotic events, association of aPL positivity with rising serum creatinine and ARDS suggest that aPL may contribute to end organ dysfunction through enhanced microthrombosis, resulting in increased mortality. (Figure Presented)
PMCID:
EMBASE:637274568
ISSN: 2326-5205
CID: 5164742
Right Ventricular Ejection Fraction for the Prediction of Major Adverse Cardiovascular and Heart Failure-Related Events: A Cardiac MRI Based Study of 7131 Patients With Known or Suspected Cardiovascular Disease
BACKGROUND:There is increasing evidence that right ventricular ejection fraction (RVEF) may provide incremental value to left ventricular (LV) ejection fraction for the prediction of major adverse cardiovascular events. To date, generalizable utility for RVEF quantification in patients with cardiovascular disease has not been established. Using a large prospective clinical outcomes registry, we investigated the prognostic value of RVEF for the prediction of major adverse cardiovascular events- and heart failure-related outcomes. METHODS:Seven thousand one hundred thirty-one consecutive patients with known or suspected cardiovascular disease undergoing cardiovascular magnetic resonance imaging were prospectively enrolled. Multichamber volumetric quantification was performed by standardized operational procedures. Patients were followed for the primary composite outcome of all-cause death, survived cardiac arrest, admission for heart failure, need for transplantation or LV assist device, acute coronary syndrome, need for revascularization, stroke, or transient ischemic attack. A secondary, heart failure focused outcome of heart failure admission, need for transplantation/LV assist device or death was also studied. RESULTS:<0.001) with a 1-year cumulative event rate of 22% versus 7% above this cutoff. CONCLUSIONS:RVEF is a powerful and independent predictor of major adverse cardiac events with broad generalizability across patients with known or suspected cardiovascular disease. These findings support migration towards biventricular phenotyping for the classification of risk in clinical practice. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04367220.
PMID: 33722059
ISSN: 1942-0080
CID: 4862112
A Pilot Open-label Study of Aldose Reductase Inhibition with AT-001 (caficrestat) in Patients Hospitalized for COVID-19 Infection: Results from a Registry-based Matched-control Analysis [Meeting Abstract]
ISI:000746754900022
ISSN: 0002-8703
CID: 5208602
COVID-19 and the Heart and Vasculature: Novel Approaches to Reduce Virus-Induced Inflammation in Patients With Cardiovascular Disease
The coronavirus disease 2019 (COVID-19) pandemic presents an unprecedented challenge and opportunity for translational investigators to rapidly develop safe and effective therapeutic interventions. Greater risk of severe disease in COVID-19 patients with comorbid diabetes mellitus, obesity, and heart disease may be attributable to synergistic activation of vascular inflammation pathways associated with both COVID-19 and cardiometabolic disease. This mechanistic link provides a scientific framework for translational studies of drugs developed for treatment of cardiometabolic disease as novel therapeutic interventions to mitigate inflammation and improve outcomes in patients with COVID-19.
PMID: 32687400
ISSN: 1524-4636
CID: 4551152
Management of Coronary Disease in Patients with Advanced Kidney Disease
BACKGROUND:Clinical trials that have assessed the effect of revascularization in patients with stable coronary disease have routinely excluded those with advanced chronic kidney disease. METHODS:We randomly assigned 777 patients with advanced kidney disease and moderate or severe ischemia on stress testing to be treated with an initial invasive strategy consisting of coronary angiography and revascularization (if appropriate) added to medical therapy or an initial conservative strategy consisting of medical therapy alone and angiography reserved for those in whom medical therapy had failed. The primary outcome was a composite of death or nonfatal myocardial infarction. A key secondary outcome was a composite of death, nonfatal myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. RESULTS:At a median follow-up of 2.2 years, a primary outcome event had occurred in 123 patients in the invasive-strategy group and in 129 patients in the conservative-strategy group (estimated 3-year event rate, 36.4% vs. 36.7%; adjusted hazard ratio, 1.01; 95% confidence interval [CI], 0.79 to 1.29; P = 0.95). Results for the key secondary outcome were similar (38.5% vs. 39.7%; hazard ratio, 1.01; 95% CI, 0.79 to 1.29). The invasive strategy was associated with a higher incidence of stroke than the conservative strategy (hazard ratio, 3.76; 95% CI, 1.52 to 9.32; P = 0.004) and with a higher incidence of death or initiation of dialysis (hazard ratio, 1.48; 95% CI, 1.04 to 2.11; P = 0.03). CONCLUSIONS:Among patients with stable coronary disease, advanced chronic kidney disease, and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of death or nonfatal myocardial infarction. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA-CKD ClinicalTrials.gov number, NCT01985360.).
PMID: 32227756
ISSN: 1533-4406
CID: 5451232
Identifying the value of RVEF for the prediction of major cardiovascular outcomes: a study of 7,131 patients undergoing cardiovascular magnetic resonance imaging [Meeting Abstract]
ISI:000606106300227
ISSN: 0195-668x
CID: 4799272
Food as Medicine for Secondary Prevention of Cardiovascular Events Following an Acute Coronary Syndrome
Cardiovascular disease is the leading cause of death in men and women in the USA. Once a patient experiences an acute coronary syndrome (ACS), they are at increased risk for hospital readmission within 30Â days and 6Â months after discharge and more importantly, they have worse survival. Hospital readmissions lead to poor clinical outcomes for the patient and also significantly increase healthcare costs due to repeat diagnostic evaluation, imaging, and coronary interventions. The goal after hospital discharge is to modify cardiovascular (CV) risk factors including hypertension, hyperlipidemia, and diabetes to prevent repeat coronary events; however, drug therapy is only one aspect. Several diets have been shown to decrease weight and reduce these risk factors over short durations; however, most people typically cannot sustain their diet and regain the weight. The Intelligent Quisine (IQ) diet is a prepared meal plan that was designed to meet the American Heart Association and American Diabetes Association nutritional guidelines and simplify the daily consumption of a nutritionally complete, calorie conscious meal. The IQ diet has been shown to significantly reduce blood pressure, cholesterol levels, glucose levels, and weight over a 10-week period. Additional studies have shown that patients are able to remain compliant on the diet for a year and maintain the reduction of their CV risk factors. If patients are consistent with a healthy calorie conscious and nutritionally complete diet modifying CV risk factors long term, then food could be as powerful in reducing CV events as evidence-based drug therapy. There is a need to begin conceptualizing food as medicine. To this end, it is time for a randomized control trial implementing the IQ diet versus current standard dietary recommendations in a large number of patients and measuring hard CV endpoints. Many readmissions can be avoided with proper patient education and support emphasizing lifestyle modifications such as eating healthy and smoking cessation on a foundation of optimal medical therapy.
PMID: 29948740
ISSN: 1573-7241
CID: 3168502
Design of the Magnetic Resonance Imaging Evaluation of Mineralocorticoid Receptor Antagonism in Diabetic Atherosclerosis (MAGMA) Trial
Mineralocorticoid receptor (MR) activation plays an essential role in promoting inflammation, fibrosis, and target organ damage. Currently, no studies are investigating MR antagonism in patients with type 2 diabetes mellitus (T2DM) with chronic kidney disease, at high risk for cardiovascular complications, who are otherwise not candidates for MR antagonism by virtue of heart failure. Further, there is limited information on candidate therapies that may demonstrate differential benefit from this therapy. We hypothesized that MR antagonism may provide additional protection from atherosclerosis progression in higher-risk patients who otherwise may not be candidates for such a therapeutic approach. In this double-blind, randomized, placebo-controlled trial, subjects with T2DM with chronic kidney disease (>/= stage 3) will be randomized in a 1:1 manner to placebo or spironolactone (12.5 mg with eventual escalation to 25 mg daily over a 4-week period). The co-primary efficacy endpoint will be percentage change in total atheroma volume in thoracic aorta and left ventricular mass at 52 weeks in patients treated with spironolactone vs placebo. Secondary outcomes include 24-hour mean systolic blood pressure, central aortic blood pressure, and insulin resistance (HOMA-IR) at 6 weeks. A novel measure in the study will be changes in candidate miRNAs that regulate expression of NR3C2 (MR gene) as well as measuring monocyte/macrophage polarization in response to therapy with spironolactone. We envision that our strategy of simultaneously probing the effects of a drug combined with analysis of mechanisms of action and predictive response will likely provide key information with which to design event-based trials.
PMID: 28555959
ISSN: 1932-8737
CID: 2802292
