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OBJECTIVE Diabetes mellitus (DM) is a major risk factor for severe coronavirus disease 2019 (COVID-19) for reasons that are unclear. RESEARCH DESIGN AND METHODS We leveraged the International Study of Inflammation in COVID-19 (ISIC), a multicenter observational study of 2,044 patients hospitalized with COVID-19, to characterize the impact of DM on in-hospital outcomes and assess the contribution of inflammation and hyperglycemia to the risk attributed to DM. We measured biomarkers of inflammation collected at hospital admission and collected glucose levels and insulin data throughout hospitalization. The primary outcome was the composite of in-hospital death, need for mechanical ventilation, and need for renal replacement therapy. RESULTS Among participants (mean age 60 years, 58.2% males), those with DM (n = 686, 33.5%) had a significantly higher cumulative incidence of the primary outcome (37.8% vs. 28.6%) and higher levels of inflammatory biomarkers than those without DM. Among biomarkers, DM was only associated with higher soluble urokinase plasminogen activator receptor (suPAR) levels in multivariable analysis. Adjusting for suPAR levels abrogated the association between DM and the primary outcome (adjusted odds ratio 1.23 [95% CI 0.78, 1.37]). In mediation analysis, we estimated the proportion of the effect of DM on the primary outcome mediated by suPAR at 84.2%. Hyperglycemia and higher insulin doses were independent predictors of the primary outcome, with effect sizes unaffected by adjusting for suPAR levels. CONCLUSIONS Our findings suggest that the association between DM and outcomes in COVID-19 is largely mediated by hyperinflammation as assessed by suPAR levels, while the impact of hyperglycemia is independent of inflammation.

Little is known about the association between tacrolimus time in therapeutic range (TTR) within the guideline-recommended targets and heart transplant (HT) patient outcomes. This study evaluated the association of early tacrolimus TTR with rejection and other clinical outcomes during an extended follow-up after HT.This was a single-center retrospective cohort study.The study was conducted at Michigan Medicine (1/1/2006-12/31/2017).HT recipients ≥18 years of age were included.The primary end point was the effect of tacrolimus TTR on time to rejection over the entire follow-up period.A total of 137 patients were included with a median follow-up of 53 months. Based on the median TTR of 58%, the patients were divided into the low tacrolimus TTR (n = 68) and high tacrolimus TTR (n = 69) cohort. The high tacrolimus TTR was associated with a significantly lower risk of rejection compared to the low tacrolimus TTR cohort (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.41-0.98; p = 0.04). A post hoc analysis revealed associations between rejection and TTR when high and low TTR groups were created at different levels. TTR30% was associated with a 7-fold higher risk of rejection (HR 7.56; 95% CI 1.76-37.6; p 0.01) and TTR75% was associated with a 77% lower risk of rejection (HR 0.23; 95% CI 0.08-0.627; p 0.01).Patients in the higher tacrolimus TTR cohort had a lower risk of rejection. We observed correlations between higher risk of rejection with TTR30% and lower risk of rejection with TTR75%. Future studies should focus on validating the optimal TTR cutoff while also exploring a cutoff to delineate high-risk patients for which early interventions to improve tacrolimus TTR may be beneficial.

Background Venous thromboembolism (VTE) contributes significantly to COVID‐19 morbidity and mortality. The urokinase receptor system is involved in the regulation of coagulation. Levels of soluble urokinase plasminogen activator receptor (suPAR) reflect hyperinflammation and are strongly predictive of outcomes in COVID‐19. Whether suPAR levels identify patients with COVID‐19 at risk for VTE is unclear. Methods and Results We leveraged a multinational observational study of patients hospitalized for COVID‐19 with suPAR and D‐dimer levels measured on admission. In 1960 patients (mean age, 58 years; 57% men; 20% Black race), we assessed the association between suPAR and incident VTE (defined as pulmonary embolism or deep vein thrombosis) using logistic regression and Fine‐Gray modeling, accounting for the competing risk of death. VTE occurred in 163 (8%) patients and was associated with higher suPAR and D‐dimer levels. There was a positive association between suPAR and D‐dimer (β=7.34; P =0.002). Adjusted for clinical covariables, including D‐dimer, the odds of VTE were 168% higher comparing the third with first suPAR tertiles (adjusted odds ratio, 2.68 [95% CI, 1.51–4.75]; P Conclusions Higher suPAR was associated with incident VTE independently of D‐dimer in patients hospitalized for COVID‐19. Combining suPAR and D‐dimer identified patients at low VTE risk. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04818866.

Objective To determine whether surge conditions were associated with increased mortality. Design Multicenter cohort study. Setting U.S. ICUs participating in STOP-COVID. Patients Consecutive adults with COVID-19 admitted to participating ICUs between March 4 and July 1, 2020. Interventions None Measurements and Main Results The main outcome was 28-day in-hospital mortality. To assess the association between admission to an ICU during a surge period and mortality, we used two different strategies: (1) an inverse probability weighted difference-in-differences model limited to appropriately matched surge and non-surge patients and (2) a meta-regression of 50 multivariable difference-in-differences models (each based on sets of randomly matched surge- and non-surge hospitals). In the first analysis, we considered a single surge period for the cohort (March 23 – May 6). In the second, each surge hospital had its own surge period (which was compared to the same time periods in matched non-surge hospitals). Our cohort consisted of 4342 ICU patients (average age 60.8 [sd 14.8], 63.5% men) in 53 U.S. hospitals. Of these, 13 hospitals encountered surge conditions. In analysis 1, the increase in mortality seen during surge was not statistically significant (odds ratio [95% CI]: 1.30 [0.47-3.58], p = .6). In analysis 2, surge was associated with an increased odds of death (odds ratio 1.39 [95% CI, 1.34-1.43], p Conclusions Admission to an ICU with COVID-19 in a hospital that is experiencing surge conditions may be associated with an increased odds of death. Given the high incidence of COVID-19, such increases would translate into substantial excess mortality.

There are few reports of HeartMate 3 pump thrombosis, with existing reports relating to outflow occlusion or early perioperative thrombosis. We present a case of late pump thrombosis requiring pump exchange.

Purpose Racial disparities in COVID-19 outcomes have been described. We sought to determine whether differences in inflammatory markers, use of COVID-19 therapies, enrollment in clinical trials, and in-hospital outcomes contribute to racial disparities between Black and non-Black patients hospitalized for COVID-19. Methods We leveraged a prospective cohort study which enrolled 1325 consecutive patients hospitalized for COVID-19, of whom 341 (25.7%) were Black. We measured biomarkers of inflammation and collected data on the use COVID-19-directed therapies, enrollment in COVID-19 clinical trials, mortality, need for renal replacement therapy, and need for mechanical ventilation. Results Compared to non-Black patients, Black patients had a higher prevalence of COVID-19 risk factors including obesity, hypertension, and diabetes mellitus, and were more likely to require renal replacement therapy (15.8% vs. 7.1%, P

Variation in hospital mortality has been described for coronavirus disease 2019 (COVID-19), but the factors that explain these differences remain unclear.Our objective was to utilize a large, nationally representative dataset of critically ill adults with COVID-19 to determine which factors explain mortality variability.In this multicenter cohort study, we examined adults hospitalized in intensive care units with COVID-19 at 70 United States hospitals between March and June 2020. The primary outcome was 28-day mortality. We examined patient-level and hospital-level variables. Mixed-effects logistic regression was used to identify factors associated with interhospital variation. The median odds ratio (OR) was calculated to compare outcomes in higher- vs. lower-mortality hospitals. A gradient boosted machine algorithm was developed for individual-level mortality models.A total of 4,019 patients were included, 1537 (38%) of whom died by 28 days. Mortality varied considerably across hospitals (0-82%). After adjustment for patient- and hospital-level domains, interhospital variation was attenuated (OR decline from 2.06 [95% CI, 1.73-2.37] to 1.22 [95% CI, 1.00-1.38]), with the greatest changes occurring with adjustment for acute physiology, socioeconomic status, and strain. For individual patients, the relative contribution of each domain to mortality risk was: acute physiology (49%), demographics and comorbidities (20%), socioeconomic status (12%), strain (9%), hospital quality (8%), and treatments (3%).There is considerable interhospital variation in mortality for critically ill patients with COVID-19, which is mostly explained by hospital-level socioeconomic status, strain, and acute physiologic differences. Individual mortality is driven mostly by patient-level factors. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Summary: Many US states published crisis standards of care (CSC) guidelines for allocating scarce critical care resources during the COVID-19 pandemic. However, the performance of these guidelines in maximizing their population benefit has not been well tested. In 2,272 adults with COVID-19 requiring mechanical ventilation drawn from the Study of the Treatment and Outcomes in Critically Ill Patients with COVID-19 (STOP-COVID) multicenter cohort, we test the following three approaches to CSC algorithms: Sequential Organ Failure Assessment (SOFA) scores grouped into ranges, SOFA score ranges plus comorbidities, and a hypothetical approach using raw SOFA scores not grouped into ranges. We find that area under receiver operating characteristic (AUROC) curves for all three algorithms demonstrate only modest discrimination for 28-day mortality. Adding comorbidity scoring modestly improves algorithm performance over SOFA scores alone. The algorithm incorporating comorbidities has modestly worse predictive performance for Black compared to white patients. CSC algorithms should be empirically examined to refine approaches to the allocation of scarce resources during pandemics and to avoid potential exacerbation of racial inequities.

Rationale & Objective Underlying kidney disease is an emerging risk factor for more severe COVID-19 illness. We examined the clinical courses of critically ill COVID-19 patients with and without pre-existing kidney disease and investigated the association between degree of underlying kidney disease and in-hospital outcomes. Study Design Retrospective cohort study Settings & Participants 4,264 critically ill COVID-19 patients (143 dialysis patients, 521 chronic kidney disease [CKD] patients, and 3,600 patients without CKD) admitted to ICUs at 68 hospitals in the United States. Predictor(s) Presence (versus absence) of pre-existing kidney disease Outcome(s) In-hospital mortality (primary); respiratory failure, shock, ventricular arrhythmia/ cardiac arrest, thromboembolic event, major bleed, and acute liver injury (secondary) Analytical Approach We used standardized differences to compare patient characteristics (values >0.10 indicate a meaningful difference between groups) and multivariable adjusted Fine and Gray survival models to examine outcome associations. Results Dialysis patients had a shorter time from symptom onset to ICU admission compared to other groups (median [quartile 1-quartile 3] days: 4 [2-9] for dialysis patients; 7 [3-10] for CKD patients; 7 [4-10] for patients without pre-existing kidney disease). More dialysis patients (25%) reported altered mental status than those with CKD (20%, standardized difference = 0.12) and no kidney disease (12%, standardized difference = 0.36). Half of dialysis and CKD patients died within 28-days of ICU admission versus 35% of patients without pre-existing kidney disease. Compared to patients without pre-existing kidney disease, dialysis patients had a higher risk of 28-day in-hospital death (adjusted HR 1.41; 95% CI 1.09, 1.81), while patients with CKD had an intermediate risk (adjusted HR 1.25; 95% CI 1.08, 1.44). Limitations Potential residual confounding Conclusions Findings highlight the high mortality of individuals with underlying kidney disease and severe COVID-19, underscoring the importance of identifying safe and effective COVID-19 therapies for this vulnerable population., Individuals with underlying kidney disease may be particularly vulnerable to severe COVID-19 illness, marked by multi-system organ failure, thrombosis, and a heightened inflammatory response. Among 4,264 critically ill adults with COVID-19 admitted to 68 intensive care units across the U.S., we found that both chronic kidney disease and dialysis patients had a ∼50% 28-day in-hospital mortality rate. Patients with underlying kidney disease had higher in-hospital mortality than patients without kidney disease, with patients on maintenance dialysis having the highest risk. As evidenced by differences in symptoms and clinical trajectories, patients with pre-existing kidney disease may have unique susceptibility to COVID-19-related complications which warrants additional study and special consideration in the pursuit and development of targeted therapies.

Introduction: There have been concerns that NSAID use may worsen outcomes in coronavirus disease 2019 (COVID-19) through upregulation of the ACE2 receptor used by the SARS-CoV-2 virus for cell entry. Hypothesis: We sought to determine whether prior use of NSAIDs in patients hospitalized with COVID-19 is associated with worse in-hospital outcomes. Methods: The Michigan Medicine Covid-19 Cohort (M 2 C 2 ) is an ongoing prospective observational study in which detailed clinical, laboratory and outcomes data were collected from chart review of consecutive adult patients hospitalized for COVID-19. Patients who were positive for SARS-CoV-2 infection but without symptoms of COVID-19 were not included in this cohort. We identified 553 patients who presented to University of Michigan Hospital between March 1 st and May 1 st for COVID-19, of whom 519 had data on whether they took NSAIDs prior to hospitalization. We examined the association between NSAID use and outcomes during their hospitalization. Results: 52 (10.0%) patients were taking NSAIDs prior to hospitalization (NSAID group; mean age 55.8 [SD 15.2]; 46.2% men) and 467 (90.0%) were not taking NSAIDs (non-NSAID group; mean age 61 [SD 16.0]; 57.7% men). There was no significant difference between the inflammatory markers on presentation to hospital between groups including CRP (median 8.0 vs median 9.7, p-value 0.79), procalcitonin (median 0.18 vs median 0.21, p-value 0.66), d-dimer (median 0.90 vs median 1.25, p-value 0.12), and IL-6 (median 36.7 vs median 49.3, p-value 0.43). All-cause mortality was not significantly different between the NSAID and non-NSAID groups (11.5% vs 16.8%, p-value 0.36) and neither was the risk of ICU admission (46.2% vs 48.9%, p-value 0.62). Conclusions: Among patients presenting to hospital with COVID-19, prior use of NSAIDs was not associated with significantly different levels of inflammatory markers on admission and was also not associated with significantly different mortality or rates of ICU admission.

Introduction: Mortality and demographic data during the COVID-19 pandemic demonstrate a disproportionate prevalence and mortality among patients identifying as Black and Native American. Hypothesis: We hypothesized minority patients would have worse COVID-19 outcomes and be less likely to receive COVID-19 specific therapies compared to Caucasian patients. Methods: We used the Michigan Medicine COVID-19 Cohort to extract treatment and outcome data on adult patients with COVID-19 who had been discharged or died by June 17 th , 2020. We calculated crude rates of COVID-19 specific treatments and outcomes between patients identifying in different racial groups using Caucasian patients as a baseline. Results: Of 553 patients analyzed, 486 patients were included, 213 (43.8%) identified as Caucasian, 232 (47.7%) identified as Black, 33 (6.8%) identified as Asian, 6 (1.2%) had an unknown racial group, and 1 identified as more than one race and 1 identified as Native American. Given this distribution, analysis was focused on Black and Caucasian patients. Black patients were less likely to receive remdesivir (3.9% vs 12.2%, P-value = 0.001) or be enrolled in COVID-19 clinical trials (10.3% vs 19.7%, P-value = 0.005). Black patients were more likely than Caucasian patients to have acute kidney injury (63.8% vs 45.5%, P-value = Conclusions: Racial disparities exist in both treatment and outcomes in COVID-19. We report a stark difference in the rate of receipt of remdesivir between Black and Caucasian patients and lower Black patient enrollment in clinical trials, matching trends in other areas of medicine. Further study is needed to determine if these differences in treatment are associated with the differential renal outcomes seen, and how comorbidities impact outcomes.

Introduction: The COVID-19 pandemic has spread across the globe and claimed many lives. Initial studies suggest that there are gender-based differences in severity of disease and mortality, with male patients having worse outcomes. We sought to further characterize gender differences to COVID-19 infection. Hypothesis: Male patients have a higher severity of illness from COVID-19. Methods: The Michigan Medicine COVID-19 Cohort (M2C2) is an ongoing prospective observational study in which detailed clinical, laboratory and outcomes data were collected from chart review of consecutive adult patients hospitalized for COVID-19. Patients who were positive for SARS-CoV-2 infection but without symptoms of COVID-19 were not included in this cohort. The M2C2registry consists of 553 patients with 491 included in this analysis. There were 282 male patients and 208 female patients. Baseline characteristics, comorbidities, and characteristics of in-patient management were compared among male and female patients. The primary outcomes analyzed were in-hospital death of any cause including dismissal to hospice, need for renal replacement therapy (RRT), need for mechanical ventilation, and hospital length of stay. Results: Significant differences were observed among various patient characteristics and outcomes across gender. While no mortality difference was present between males and females, 43.8% of male patients were diagnosed with ARDS compared to 35.1% of female patients. The average days on mechanical ventilation were greater for male ICU patients (4.1 ± 5.91 vs. 3.4 ± 5.75) and the length of stay (days) was also longer for males (13.6 ± 11.94 vs. 12.2 ± 12.29). Admission creatinine was higher in males compared to females (2.95 ± 12.97 vs. 1.31 ± 1.33) and more male patients required RRT during their ICU admission (19.5% vs. 10.6%). Conclusions: While no difference in in hospital mortality was observed across gender, the severity of disease was greater among male patients in regards to ARDS, the need for ventilatory support, and kidney injury with requirement for RRT.

Background: Secondary infections occur in 10-15% of critically ill sepsis patients. Anecdotal reports suggest secondary infections are common in coronavirus disease 2019 (COVID-19), however data are lacking. We examine the rate of secondary infections in hospitalized patients with COVID-19 and its impact on the cytokine surge and in-hospital outcomes. Methods: The Michigan Medicine Covid-19 Cohort (M2C2) is an ongoing prospective observational study in which detailed clinical, laboratory and outcome data were collected from chart review of consecutive adult patients hospitalized for COVID-19. Patients who were positive for SARS-CoV-2 infection but without respiratory symptoms were not included in this cohort. We define secondary infections as physician-diagnosed and treated bacterial or viral infections secondary to SARS-CoV-2. Results: Of 553 COVID-19 patients hospitalized at Michigan Medicine, 191 (34.5%) developed a secondary infection during hospitalization. The mean age of patients with a secondary infection was 60 years, 61.3% were male compared to 58.8 years, 53.5% male in patients with no secondary infection. Bacterial pneumonia, including ventilator-associated pneumonia, was the most prevalent secondary infection among hospitalized patients (78.5%). Other secondary infections included urosepsis (14.1%), bacteremia (16.8%), and 17.3% of patients developed other types of infections such as shingles and clostridium difficile. 25.8% of patients without secondary infections received antibiotics during their admission compared to 47.1% of patients with secondary infections. Multiple secondary infections (>1) occurred in 43 (8.2%) of patients. Patients with secondary infections were more likely to develop acute kidney injury (78.0% vs. 38.3%, p Conclusions: Secondary infections are common in hospitalized patients with COVID-19 and are associated with life-threatening complications and high mortality. This study suggests that secondary infection prevention may be especially important in COVID-19 patients.

Introduction: COVID-19 is caused by infection with SARS-CoV2 which uses ACE2 as its host receptor. RAS inhibitors such as ACE-inhibitors and ARBs (ACEI/ARB) may increase ACE2 levels. ACE2 levels may also have a lung protective role in ARDS. There is concern over the safety of using these medications in patients with COVID-19. Hypothesis: To characterize the association of a history of ACEI/ARB use by hospitalized patients with COVID-19 and with in-hospital outcomes. Methods: The Michigan Medicine Covid-19 Cohort (M 2 C 2 ) is an ongoing prospective observational study in which detailed clinical, laboratory and outcomes data were collected from chart review of consecutive adult patients hospitalized for COVID-19. Patients who were positive for SARS-CoV-2 infection but without symptoms of COVID-19 were not included in this cohort. We identified 490 patients admitted between March 1 st and May 1 st for COVID-19, of whom all 490 had data on whether they took ACEI/ARB prior to hospitalization. We examined the association between ACEI/ARB use and all-cause death, respiratory failure and acute kidney injury (AKI) during their hospitalization. Results: 175 (35.7%) patients were taking ACEI/ARB prior to hospitalization (ACEI/ARB group; mean age 63.6 [SD 13.9]; 64% men) and 315 (64.3%) were not taking ACEI/ARB (non-ACEI/ARB group; median age 58.6 [SD 16.1]; 54.3% men). The risk of developing ARDS was not significantly different between the ACEI/ARB group and non-ACEI/ARB group (47.4% vs 43.5%, p-value 0.53) and neither was the risk death (15.4% vs 16.8%, p-value 0.97), despite a higher prevalence of comorbidities in the ACEI/ARB group including hypertension (96.6% vs 51.4%, p-value Conclusions: Among hospitalized patients with COVID-19, prior to hospitalization use ACEI/ARB was not associated with significantly different risk of ARDS or mortality despite having higher rates of comorbidities in the ACEI/ARB group.

Background Since coronavirus disease 2019 (COVID-19) was first identified in Wuhan, China, in December 2019, the number of cases has risen exponentially. Clinical characteristics and outcomes among patients with orthotopic heart transplant (OHT) with COVID-19 remain poorly described. Methods We performed a retrospective case series of patients with OHT with COVID-19 admitted to 1 of 2 hospitals in Southeastern Michigan between March 21 and April 22, 2020. Clinical data were obtained through review of the electronic medical record. Final date of follow-up was May 7, 2020. Demographic, clinical, laboratory, radiologic, treatment, and mortality data were collected and analyzed. Results We identified 13 patients with OHT admitted with COVID-19. The mean age of patients was 61 ± 12 years, 100% were black males, and symptoms began 6 ± 4 days before admission. The most common symptoms included subjective fever (92%), shortness of breath (85%), and cough (77%). Six patients (46%) required admission to the intensive care unit. Two patients (15%) died during hospitalization. Conclusions Black men may be at increased risk for COVID-19 among patients with OHT. Presenting signs and symptoms in this cohort are similar to those in the general population. Elevated inflammatory markers on presentation appear to be associated with more severe illness.

Background Systemic inflammation during implant of a durable left ventricular assist device (LVAD) may contribute to adverse outcomes. We investigated the association of the preoperative inflammatory markers with subsequent right ventricular failure (RVF). Materials and methods Prospective data was collected on 489 patients from 2003 through 2017 who underwent implantation of a durable LVAD. Uni- and multivariable correlation with leukocytosis was determined using linear and binary logistic regression. The population was also separated into low ( 10.5 K/ul, n = 127) white blood cell count (WBC) groups. Mantel-Cox statistics was used to analyze survival data. Results Postop RVF was associated with a higher preop WBC (11.3 + 5.7 vs 8.7 + 3.1) and C-reactive protein (CRP, 5.6 + 4.4 vs 3.3 + 4.7) levels. Multivariable analysis identified an independent association between increased WBC preoperatively with increased lactate dehydrogenase (LDH, P

The effect of significant mitral regurgitation (MR) on outcomes after continuous flow left ventricular assist device (cfLVAD) implantation remains unclear.We performed a retrospective review of prospectively collected data from 159 patients with preoperative severe MR who underwent cfLVAD implantation (2003-2017). Two-step cluster analysis using the log-likelihood distance for post-cfLVAD implantation parameters, which included right ventricular (RV) dysfunction, MR severity, and tricuspid regurgitation (TR) severity. Post-cfLVAD implantation echocardiographic parameters were obtained within the first month.Cluster analysis resulted in 3 groups. Group 1 (n = 67) had mild or less MR with moderate-severe RV dysfunction (RVD). Group 2 (n = 43) had moderate-severe MR with moderate-severe RVD. Group 3 (n = 49) had moderate MR with mild RVD. Group 2 had the largest proportion with Interagency Registry for Mechanically Assisted Circulatory Support score of 1 (30.2%) and 2 (41.9%). They were more likely to undergo temporary mechanical circulatory support (18.6%) and tricuspid valve procedure (62.8%). Group 2 had the highest rate of stroke (30.2%; P = .02), hemolysis (39.5%; P = .01), device thrombosis (30%; P = .01), and worst survival (46.5%; P = .01). Survival at 5 years for groups 1, 2, and 3 were 56.0%, 17.6%, and 55.8%. Regression analysis of the entire population showed that greater MR severity after cfLVAD was associated with RV failure (P .05; odds ratio, 1.6) and RV assist device use (P = .09; odds ratio, 1.6). After excluding tricuspid valve repairs, MR severity had a positive correlation with TR severity (R = 0.33; P .01).After cfLVAD implantation, moderate-severe MR and RVD predicted RV failure. Patients with preoperative moderate-severe MR and TR coupled with moderate-severe RVD might benefit the most from mitral and tricuspid valve intervention.

Heart failure epidemic has been on the rise over the last few decades. With limited organ donors, the number of left ventricular assist device implantation (LVAD) has been on the rise. LVAD support comes with different complications including right ventricular failure (RVF). The incidence of RVF post LVAD implantation is estimated to be around 10–40%. Mechanism of RVF post LVAD implantation has a complex pathophysiology that involves patient hemodynamics, biochemical profile, comorbidities, and pump mechanics. Predicting RVF has been an extensive area of research. Multiple risk scores have been developed to predict RVF post-op and the need of a right ventricular assist device. Moreover, multiple echocardiographic and hemodynamic parameters have been reported in the literature that could predict RVF. After diagnosis, management of RVF remains complex and involves judicious optimization of hemodynamics and biochemical profile in the perioperative period. Despite optimal management many patients will end up developing chronic RVF, which has been associated with worse outcome even among patients undergoing heart transplantation. Additionally, RVF has been reported to be a strong risk factor for acute kidney injury and progression to renal failure post LVAD implantation. This chapter reviews the pathophysiology, diagnosis, and management of RVF post LVAD implantation.

Factor XIII (FXIII) is necessary for cross linking of fibrin strands and generation of stable fibrin clot. FXIII Val34Leu is a common genetic single nucleotide polymorphism that has been associated with accelerated fibrin stabilization and reduced rate of fibrinolysis. The contribution of Val34Leu to long term risk of recurrent myocardial infarction (MI) in patients with coronary stenting has not been conclusively established. The objective of the study was to examine the effects of Val34Leu on fibrin generation, platelet aggregation, and long term clinical outcomes in patients with coronary artery disease treated with dual antiplatelet therapy. Patients with angiographically documented coronary artery disease who were treated with aspirin and clopidogrel were enrolled (n = 211). Light transmittance aggregometry and plasma fibrin clot formation using thrombelastography (TEG) were determined. Genotyping of Val34Leu was performed using Taqman assay. Clinical events during follow up were recorded. Homozygous carriers of 34 Leu variant had significantly shorter fibrin clot formation time as compared to wild type individuals (TEG K: 1.27 ± 0.3 vs. 1.68 ± 1.1 min, p = 0.011). The Val34Leu variant was associated with gene dose dependent increased risk of MI (log rank, p = 0.002) or occurrence of composite of MI and CV death (log rank, p = 0.005) with highest event rates observed in homozygous carriers of 34 Leu. In summary, FXIII Val34Leu polymorphism was associated with increased rate of fibrin stabilization in homozygous carriers of the variant and may increase risk of recurrent MI and death in patients with angiographically established coronary artery disease treated with dual antiplatelet therapy.

Introduction The number of patients with stage D heart failure (HF) requiring a left ventricular assist device (LVAD) is on the rise. The aim herein is to examine family medicine (FM), internal medicine (IM) faculty and house officers (HO) understanding and experience about LVAD. Methods A survey was distributed by email to FM, IM faculty and HO at the University of Michigan. The survey contained questions about LVAD survival and basic management of arresting LVAD patients. Results 111 completed the survey (23.8%). Respondents self-identified as HO (59.5%) and the rest were FM and IM faculty. Only 30.9% reported receiving education on LVADs during their training and 66.6% reported being somewhat familiar with LVAD therapy. However, only half felt that LVAD therapy is a good option for improving quality of life and only 32% felt that LVADs improved survival. Only 6% of respondents estimated correct 1-year survival post pump implant. 77% correctly identified the anticoagulation of choice and 47% reported the appropriate way to measure blood pressure. No respondents received instruction on how to run a code on LVAD patients during ACLS certification, only 6.3% were aware of the recent AHA scientific statement regarding unresponsive LVAD patient management, and only 9% felt comfortable running a code blue on an LVAD patient. 49% and 35%, respectively, report that chest compressions and defibrillation can be performed if indicated. HO had better knowledge than IM and FM faculty regarding arresting LVAD patient management (p Conclusions Substantial knowledge gaps about LVAD and basic LVAD management were identified among IM, FM faculty and HO at a large teaching hospital. Similar knowledge gaps may exist among the larger internal and family medicine communities as a whole.

Clinical Development Phases I-III Regulatory, Quality, Manufacturing Thrombelastography (TEG) is a viscoelastic assay method used to assess whole blood and plasma coagulation kinetics. Specialized platelet mapping assays have been developed for the TEG platform to quantify the extent of platelet inhibition derived from P2Y12 receptor inhibitors, glycoprotein IIb/IIIa inhibitors, and aspirin. In this review, we describe the current evidence and summarize the data supporting the use of TEG in patients with cardiovascular disease. High thrombin- or adenosine diphosphate (ADP)-induced whole blood maximal clot strength (MA) has been associated with increased risk of ischemic events after percutaneous coronary interventions (PCI) and coronary artery bypass grafting (CABG). We discuss the data linking an increased clot strength phenotype with changes in metabolic and inflammatory markers. In addition, the data supporting the role of TEG in identifying subjects at risk for hemorrhagic complications while treated with dual antiplatelet therapy or while undergoing cardiac surgery is reviewed. In summary, TEG may provide additional information combining coagulation and platelet measurements within one assay, as compared with traditional coagulation or platelet assays. Further research is warranted to establish the role of TEG in personalized medicine treatment protocols.

Background: Cardiovascular involvement among patients with primary systemic amyloidosis (AL) is common and predicts poor prognosis. Different parameters have been used to predict outcome. We studied the prognostic significance of clinical, ECG and echocardiographic parameters of 60 patients with tissue proven primary cardiac amyloidosis. Method and Results: Records of 60 patients with primary amyloidosis and cardiac involvement documented by endomyocardial tissue biopsy were retrospectively evaluated. Patients mean age was 57.9 ± 10.2 years. 71.6% were male and 86.6% Caucasian. Patients’ median survival was 12.2 ± 4.4 months with only 50% of patients survived for more than 1 year. 60% of patients had CHF (NYHA II-IV). CHF (NYHA II-IV), IVS, LVPW and LVEF were significant on univariate survival analysis (p

Pump thrombosis and hemolysis in patients with left ventricular assist devices (LVADs) are associated with significant morbidity and mortality. Intensification of anticoagulation has been suggested as potential therapy, with mixed results. The aim of this study is to assess the safety and efficacy of adding eptifibatide with or without an anticoagulation agent in managing patients with LVAD presenting with hemolysis and suspected pump thrombosis. This retrospective single center study included all patients who presented with their first episode of suspected pump thrombosis and were treated with eptifibatide with or without an anticoagulant between March 1, 2011 and July 30, 2015. A total of 27 patients (23 HeartMate II, 4 HeartWare) were identified. The average age was 55 years (range 19-75) and time from implant to event averaged 513 days (range 35-1760). The average lactate dehydrogenase on presentation was 1111 and 63% of patients had power elevations. The average international normalized ratio (INR) on admission was 2.4, with INR of ≥2 in 21/27 patients. All patients received eptifibatide: 10 received eptifibatide only, 9 received eptifibatide and argatroban, and 8 received eptifibatide and heparin. Warfarin was continued in 25/27 patients. Overall, 21 patients (77.8%) were successfully treated medically, 5 (18.5%) underwent pump exchange, and 1 (3.7%) died. There were no differences in outcomes or complications between the three treatment groups. Despite initial success, 12/21 patients developed repeat episodes of hemolysis at 1 year. The 1-year survival in the patients treated medically was 90% and surgically was 60%. Our experience indicates that medical therapy for hemolysis and suspected LVAD thrombosis with warfarin and eptifibatide alone or in combination with argatroban or heparin appears safe and may be effective, although the episodes of recurrent hemolysis after medical management remain high.

Introduction Sacubitril/valsartan is a novel medication that acts as a neprilysin and angiotensin receptor blocker. It is recommended by the American College of Cardiology(ACC)/American Heart Association(AHA)/Heart Failure Society of America(HFSA) to reduce morbidity and mortality in patients with reduced ejection fraction (HFrEF) and NYHA class II or III symptoms. The main clinical trial for sacubitril/valsartan, PARADIGM-HF, employed a run-in phase which likely underestimated the side effects. The objective of this study was to compare the incidence of adverse events, medication discontinuation, or medication dose reduction in patients with HFrEF initiated on therapy with an ACE inhibitor, ARB, or sacubitril/valsartan. Methods A retrospective cohort study was conducted from July 7, 2015 to December 31, 2017. Patients 18 years of age and older with a diagnosis of HFrEF ( Results Of the patients included (n=400), 195 were started on sacubitril/valsartan and 205 on an ACE inhibitor or ARB. The sacubitril/valsartan cohort was younger (57±14 vs. 64±15; p Conclusion Patients started on sacubitril/valsartan had a significant increase in the composite endpoint compared to those started on ACE inhibitors or ARBs. Differences in adverse events in this real-world study were mainly driven by dose reduction and hyperkalemia.

Background Current guidelines recommend that caffeinated products should be avoided for at least 12 hours prior to regadenoson administration. We intended to examine the effect of caffeine consumption and of timing of last dose on hemodynamic effects after regadenoson administration for cardiac stress testing. Methods 332 subjects undergoing regadenoson stress testing were enrolled. Baseline characteristics, habits of coffee/caffeine exposure, baseline vital signs and change in heart rate, blood pressure, percent of maximal predicted heart rate, and percent change in heart rate were prospectively collected. Results Non-coffee drinkers (group 1) (73 subjects) and subjects who last drank coffee >24 hours (group 3) (139 subjects) prior to regadenoson did not demonstrate any difference in systolic blood pressure, heart rate change, maximal predicted heart rate and percent change in heart rate. Systolic blood pressure change (15.2±17.1 vs. 7.2±10.2 mmHg, p = 0.001), heart rate change (32.2±14 vs. 27.3±9.6 bpm, p = 0.038) and maximal predicted heart rate (65.5±15.6 vs. 60.7±8.6%, p = 0.038) were significantly higher in non-coffee drinkers (group 1) compared to those who drank coffee 12–24 hours prior (group 2) (108 subjects). Subjects who drank coffee >24 hours prior (group 3) exhibited higher systolic blood pressure change (13±15.8 vs. 7±10.2, p = 0.007), and heart rate change (32.1±15.3 vs. 27.3±9.6, p = 0.017) as compared to those who drank coffee 12–24 hours prior to testing (group 2). Conclusions Caffeine exposure 12–24 hours prior to regadenoson administration attenuates the vasoactive effects of regadenoson, as evidenced by a blunted rise in heart rate and systolic blood pressure. These results suggest that caffeine exposure within 24 hours may reduce the effects of regadenoson administered for vasodilatory cardiac stress testing.

Background: Improvement in left ventricular ejection fraction (LVEF) can occur with prompt treatment of the culprit arrhythmia in patients with arrhythmia-induced cardiomyopathy (AIC). Predictors of recovery, however, are not well understood. We assessed the impact of arrhythmia duration and index

Background Accurate determination of left ventricular filling pressure is essential for differentiation of pre-capillary pulmonary hypertension (PH) from pulmonary venous hypertension (PVH). Previous data suggest only a poor correlation between left ventricular end-diastolic pressure (LVEDP) and its commonly used surrogate, the pulmonary capillary wedge pressure (PCWP). However, no data exist on the diagnostic accuracy of PCWP in veterans. Furthermore, the effects of age and comorbidities on the PCWP-LVEDP relationship remain unknown. Methods We investigated the PCWP-LVEDP relationship in 101 patients undergoing simultaneous right and left heart catherization at a large VA hospital. PCWP performance was evaluated using correlation and Bland-Altman analyses. Area under Receiver Operating Characteristics curves (AUROC) for PCWP were determined. Results PCWP-LVEDP correlation was moderate (r = 0.57). PCWP-LVEDP calibration was poor (Bland-Altman limits of agreement −17.2 to 11.4 mmHg; mean bias −2.87 mmHg). 59 patients (58.4%) had pulmonary hypertension; 15 (25.4%) of those met pre-capillary PH criteria based on PCWP. However, if LVEDP was used instead of PCWP, 7/15 patients (46.6%) met criteria for PVH rather than pre-capillary PH. When restricting analysis to patients with a mean pulmonary artery pressure of ≥25 mmHg and pulmonary vascular resistance of >3 Wood units (n = 22), 10 patients (45.4%) were classified as pre-capillary PH based on PCWP ≤15 mmHg. However, if LVEDP was used, 4/10 patients (40%) were reclassified as PVH. Among patients with any type of pulmonary hypertension, PCWP discriminated moderately between high and normal LVEDP (AUROC, 0.81; 95%CI 0.69–0.94). PCWP-LVEDP correlation was particularly poor in patients with COPD or obesity. Conclusion Reliance on PCWP rather than LVEDP results in misclassification of veterans as having pre-capillary PH rather than PVH in almost 50% of cases. This is clinically relevant, as misclassification may lead to inappropriate therapies and adverse events.

Celiac disease (CD) is now recognized as a common disorder among Middle Eastern (ME) and North African (NA) populations. The aim of this review is to assess the available data regarding CD in the ME and NA and to compare this information with that of Western countries. A literature review was performed using the electronic databases PubMed and Medline (1950-2008) as search engines, and “celiac disease” was used as a Mesh term. The search was limited to ME and NA countries. The prevalence of CD in ME and NA countries among low risk populations is similar to that of Western countries, but is higher in high risk populations such as those with type 1 diabetes. It is underestimated because of lack of clinical suspicion and lack of patient awareness. Clinical presentations in term of gastrointestinal, hematologic, skeletal, and liver manifestations are similar between both populations except for a high prevalence of short stature in some ME and NA countries. Few studies have addressed atypical or silent CD. As in the West, diagnosis is initially made by serological tests and is confirmed by small intestinal biopsies. Gluten-free diet is the main mode of treatment with a higher apparent adherence rate than in the West. Most disease complications result from malabsorption. The disease is strongly associated with HLA DQ2 and to a lesser extent with HLA DQ8 alleles. In conclusion, CD prevalence is underestimated, with little data available about its malignant complications. Disease parameters in the ME and NA are otherwise similar to those in Western countries.