Faculty Bibliography

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 1500 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.

Impaired oxidative metabolism is one of multi-variate factors leading to exercise intolerance in heart failure patients. The purpose of the study was to demonstrate the use of dynamic ³¹P magnetic resonance spectroscopy (MRS) and ³¹P magnetic resonance imaging (MRI) techniques to measure PCr resynthesis rate post-exercise as a biomarker for oxidative metabolism in skeletal muscle in HF patients and controls. In this prospective imaging study, we recruited six HF patients and five healthy controls. The imaging protocol included ³¹P-MRS, spectrally selective 3D turbo spin echo for ³¹P-MRI, and Dixon multi-echo GRE for fat-water imaging on a 3 T clinical MRI scanner. All the subjects were scanned pre-exercise, during plantar flexion exercise, and post-exercise recovery, with two rounds of exercise for ³¹P -MRS and ³¹P-MRI, respectively. Unpaired t-tests were used to compare ³¹P-MRS and ³¹P-MRI results between the HF and control cohorts. The results show that PCr resynthesis rate was significantly slower in the HF cohort compared to the controls using ³¹P-MRS (P = 0.0003) and ³¹P-MRI (P = 0.0014). ³¹P-MRI showed significant differences between the cohorts in muscle groups (soleus (P = 0.0018), gastrocnemius lateral (P = 0.0007) and gastrocnemius medial (P = 0.0054)). The results from this study suggest that ³¹P-MRS/³¹P-MRI may be used to quantify lower leg muscle oxidative metabolism in HF patients, with ³¹P-MRI giving an additional advantage of allowing further localization of oxidative metabolism deficits. Upon further validation, these techniques may serve as a potentially useful clinical imaging biomarker for staging and monitoring therapies in HF-patients.

Purpose: During the COVID 19- pandemic, there is no consensus on management strategies for treating infected heart transplant patients. The outcomes of these patients vary by institution. We report our center experience and management strategies to date.
Method(s): All patients who received heart transplantation, from January 4th 2018 to September 25th 2020 and were diagnosed with SARS-CoV-2 were included and full chart review was performed.
Result(s): There were 113 heart transplants at our institution by September 2020. A total of 13 (12%) patients were infected with SARS-CoV-2: 9 (69%) isolated heart, 3 heart -kidney (23%) and 1 heat- lung (8%). The median (IQR) time from transplant to diagnosis was 10 (5-16) months. The mean age was 57 years and 50% were male; 50% were of Hispanic ethnicity. The main presenting symptoms were fever (43%), cough (86%) and SOB (43%). Chest x-ray was abnormal in all patients. We evaluated all patients and 79% were hospitalized and 21% were closely monitored as outpatients. None of our patients were hospitalized at outside institutions. Two (14%) required intubation and none required V-V ECMO support. The immunotherapy was modified in all patients: MMF and prednisone were discontinued, tacrolimus dose was reduced. COVID19 treatment was: 71% received hydroxychloroquine, 50% azithromycin, 15% remdesevir, 7% convalescent plasma. All hospitalized patients received anticoagulation. One patient had 2R/3A rejection within 30 days prior to diagnosis. Graft function was maintained in all patients with median LVEF% 65 (59-65%) except one patient who had received thymoglobulin 2 weeks prior to COVID 19 infection (LVEF 30%). The patient had a prolonged intubation but ultimately recovered and was discharged from the hospital. The one death (7.1%) was a heart - kidney recipient who concomitantly presented with pseudomonas sepsis and severe neutropenia. The remaining patients have all been discharged home.
Conclusion(s): We present our single center experience in managing COVID 19 infected heart transplant patients. We implemented uniform management strategies by incorporating aggressive reduction of immunosuppression, frequent scheduled contacts with infected outpatients and making sure all infected patients requiring hospitalization were treated at a transplant center.
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OBJECTIVE:Hydroxychloroquine (HCQ) is a mainstay of therapy in the treatment of SLE. The effect of HCQ on platelets and vascular health is uncertain. We investigated the relationship between HCQ use and dose with platelet activity, platelet transcriptomics and vascular health in patients with SLE. METHODS:Platelet aggregation, platelet mRNA expression and vascular health (sublingual capillary perfused boundary region (PBR), red blood cell filling (RBCF) and brachial artery reactivity testing) were analysed by HCQ use and dose. RESULTS:Among 132 subjects with SLE (age: 39.7±12.9 years, 97% female), 108 were on HCQ. SLE disease activity was similar between subjects on and off HCQ. Platelet aggregation in response to multiple agonists was significantly lower in patients on HCQ. There were inverse relationships between HCQ dose and gene expression pathways of platelet activity. Gene expression of P-selectin (SELP) was inversely correlated with HCQ dose (r=-0.41, p=0.003), which was validated at the protein level. Subjects on HCQ had improved vascular function correlating with HCQ dose as measured by lower PBR (r=-0.52, p=0.007), higher RBCF (r=0.55, p=0.004) and greater brachial artery reactivity (r=0.43, p=0.056). CONCLUSION/CONCLUSIONS:HCQ use was associated with decreased platelet activation and activation-related transcripts and improved vascular health in SLE.

BACKGROUND:Heart failure (HF) affects ∼5.7 million United States adults and many of these patients develop non-cardiac disease that requires surgery. The aim of this study was to determine perioperative outcomes associated with HF in a large cohort of patients undergoing in-hospital non-cardiac surgery. METHODS:Adults ≥18 years old undergoing non-cardiac surgery between 2012-2014 were identified using the HCUP National Inpatient Sample. Patients with HF were identified by ICD-9 diagnosis codes. The primary outcome was all-cause in-hospital mortality. Multivariable logistic regression models were used to estimate associations between HF and outcomes. RESULTS:A total of 21,560,996 surgical hospitalizations were identified, of which 1,063,405 (4.9%) had a diagnosis of HF. Among hospitalizations with HF, 4.7% had acute HF, 11.3% had acute on chronic HF, 27.8% had chronic HF, and 56.2% had an indeterminate diagnosis code that did not specify temporality. In-hospital perioperative mortality was more common with a diagnosis of any HF compared to without HF (4.8% vs. 0.78%, p < 0.001; adjusted OR [aOR] 2.15 [95% CI 2.09-2.22]), and the association between HF and mortality was greatest at small and non-teaching hospitals. Acute HF without chronic HF was associated with 8.0% mortality. Among patients with a chronic HF diagnosis, perioperative mortality was greater in those with acute on chronic HF compared to chronic HF alone (7.8% vs. 3.9%, p < 0.001; aOR 1.78, 95% CI 1.67-1.90). CONCLUSION/CONCLUSIONS:In patients hospitalized for non-cardiac surgery, HF was common and was associated with increased risk of perioperative mortality. The greatest risks were in patients with acute HF.