In vivo and in vitro studies establishing haptoglobin as a major susceptibility gene for diabetic vascular disease

Rabea Asleh, Andrew P LevyFaculty of Medicine, Technion-Israel Institute of Technology, Haifa, IsraelAbstract: Hemoglobin (Hb) released during hemolysis is a potent oxidant. Extracorpuscular Hb may enter the vessel wall and mediate low-density lipoprotein oxidation, thereby promoting the development and progression of atherosclerosis. Haptoglobin (Hp) is an antioxidant protein as a result of its ability to bind Hb and block Hb-induced oxidative damage. Hp also facilitates the removal of Hb from the extravascular compartment via the CD163 macrophage scavenger receptor. In man, there are two common alleles for Hp denoted 1 and 2, and correspondingly, three different possible genotypes: Hp1-1, Hp2-1, and Hp2-2. We have recently demonstrated in several longitudinal studies that Hp genotype is an independent risk factor for diabetic vascular complications. Specifically, we have shown that diabetic individuals with Hp 2-2 are more likely to develop nephropathy, retinopathy, and cardiovascular disease as compared with those with Hp2-1 or Hp1-1. Mechanistically, we have found significant Hp type differences in the antioxidant and CD163-mediated scavenging and activation functions of the different Hp protein types. Furthermore, we have demonstrated that these functions are modified in the diabetic state. In this review, we focus on the clinical studies associating the Hp polymorphism and diabetic vascular complications, and the molecular basis behind this interaction.Keywords: diabetes, cardiovascular disease, haptoglobin polymorphism, hemoglobin, oxidative stres

Divergent Effects of α-Tocopherol and Vitamin C on the Generation of Dysfunctional HDL Associated with Diabetes and the Hp 2-2 Genotype

The haptoglobin (Hp) 2-2 genotype is associated with increased risk of cardiovascular disease (CVD) in diabetes (DM). We recently proposed this increased risk arises from the tethering of redox active hemoglobin (Hb) to high density lipoprotein (HDL), thereby resulting in oxidative modification of HDL. Clinical trials have demonstrated that vitamin E (α-tocopherol) decreases while vitamin C increases CVD in Hp 2-2 DM individuals. We sought to test the hypothesis that the interaction of α-tocopherol or vitamin C on CVD in Hp 2-2 DM was due to their divergent effects on HDL oxidation and function. Vitamin C significantly increased while α-tocopherol completely blocked oxidation mediated by glycosylated Hb-Hp 2-2. Vitamin C had no benefit while α-tocopherol completely restored HDL function in Hp 2-2 DM mice. Co-administration of vitamin C mitigated the protective effects of α-tocopherol on HDL. There exists a pharmacogenomic interaction between vitamin C and α-tocopherol and the Hp 2-2 genotype on HDL function and structure. Choosing the correct antioxidant in the correct subset of patients may be critical in order to demonstrate benefit from antioxidant therapy. Antioxid. Redox Signal. 12, 209–218

Trends and Outcomes of Device-Related 30-Day Readmissions After Left Ventricular Assist Device Implantation

BACKGROUND: Left ventricular assist devices (LVAD) improve morbidity and mortality in end-stage heart failure patients, but high rates of readmissions remain a problem after implantation. We aimed to assess the incidence, trends, outcomes, and predictors of device-related 30-day readmissions after LVAD implantation. METHODS: The National Readmission Database was used to identify patients who underwent LVAD implantation between 2012 and 2017 and those with 30-day readmissions. RESULTS: The analysis included a total of 16499 adults who survived the index hospitalization for LVAD implantation. Among those, 28.1% were readmitted at 30 days, and the readmission rate has been grossly stable during the study period. Most of the readmissions occurred in the first 15 days after discharge from the index admission. The most frequent cause of readmissions was gastrointestinal bleeding (14.9% of readmissions), followed by heart failure, arrhythmias, device infection, and device thrombosis. Among reasons for readmission, intracranial bleeding was associated with highest mortality (37.6%), followed by device thrombosis (13.1%), and ischemic stroke (7.6%). Intracranial bleeding and device thrombosis were associated with lengthier stay (20.4 and 15.5 days, respectively). Readmission rates for gastrointestinal bleeding decreased, whereas device infection increased. Multivariate logistic regression model revealed the length of stay, oxygen dependence, gastrointestinal bleeding at index admission, depression and ECMO, private insurance as independent predictors of 30-day readmission. CONCLUSION: Over one-fourth of LVAD recipients have 30-day readmissions, with most of them occurring within 15 days. Most frequent cause of readmission was gastrointestinal bleeding, which was associated with the lowest in-hospital mortality among other complications

Severe Acute Myocarditis after the Third (Booster) Dose of mRNA COVID-19 Vaccination

Vaccination with mRNA vaccines against coronavirus disease 2019 (COVID-19) has been associated with a risk of developing myocarditis and pericarditis, with an estimated standardized incidence ratio of myocarditis being 5.34 (95% CI, 4.48 to 6.40) as compared to the expected incidence based on historical data according to a large national study in Israel. Most cases of myocarditis in vaccine recipients occur in young males, particularly following the second dose, and the presentation is usually mild. Recently, the third (booster) dose has been shown to reduce confirmed infections and severe illness even against common variants of the virus. In Israel, over 4.4 million citizens (more than 45% of the population) have been vaccinated with the third dose of Pfizer-BioNTech vaccine BNT162b2. Herein, we report the first case of a histologically confirmed severe myocarditis following the third dose of BNT162b2 COVID-19 vaccine

Exploring the Mechanisms Underlying the Cardiotoxic Effects of Immune Checkpoint Inhibitor Therapies

Adaptive immune response modulation has taken a central position in cancer therapy in recent decades. Treatment with immune checkpoint inhibitors (ICIs) is now indicated in many cancer types with exceptional results. The two major inhibitory pathways involved are cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed cell death protein 1 (PD-1). Unfortunately, immune activation is not tumor-specific, and as a result, most patients will experience some form of adverse reaction. Most immune-related adverse events (IRAEs) involve the skin and gastrointestinal (GI) tract; however, any organ can be involved. Cardiotoxicity ranges from arrhythmias to life-threatening myocarditis with very high mortality rates. To date, most treatments of ICI cardiotoxicity include immune suppression, which is also not cardiac-specific and may result in hampering of tumor clearance. Understanding the mechanisms behind immune activation in the heart is crucial for the development of specific treatments. Histological data and other models have shown mainly CD4 and CD8 infiltration during ICI-induced cardiotoxicity. Inhibition of CTLA4 seems to result in the proliferation of more diverse T0cell populations, some of which with autoantigen recognition. Inhibition of PD-1 interaction with PD ligand 1/2 (PD-L1/PD-L2) results in release from inhibition of exhausted self-recognizing T cells. However, CTLA4, PD-1, and their ligands are expressed on a wide range of cells, indicating a much more intricate mechanism. This is further complicated by the identification of multiple co-stimulatory and co-inhibitory signals, as well as the association of myocarditis with antibody-driven myasthenia gravis and myositis IRAEs. In this review, we focus on the recent advances in unraveling the complexity of the mechanisms driving ICI cardiotoxicity and discuss novel therapeutic strategies for directly targeting specific underlying mechanisms to reduce IRAEs and improve outcomes

Severe Acute Myocarditis after the Third (Booster) Dose of mRNA COVID-19 Vaccination

Vaccination with mRNA vaccines against coronavirus disease 2019 (COVID-19) has been associated with a risk of developing myocarditis and pericarditis, with an estimated standardized incidence ratio of myocarditis being 5.34 (95% CI, 4.48 to 6.40) as compared to the expected incidence based on historical data according to a large national study in Israel. Most cases of myocarditis in vaccine recipients occur in young males, particularly following the second dose, and the presentation is usually mild. Recently, the third (booster) dose has been shown to reduce confirmed infections and severe illness even against common variants of the virus. In Israel, over 4.4 million citizens (more than 45% of the population) have been vaccinated with the third dose of Pfizer-BioNTech vaccine BNT162b2. Herein, we report the first case of a histologically confirmed severe myocarditis following the third dose of BNT162b2 COVID-19 vaccine

Management of heart failure with reduced ejection fraction: challenges in patients with atrial fibrillation, renal disease and in the elderly

Heart failure with reduced ejection fraction (HFrEF) is an increasing global pandemic affecting more than 30 million individuals worldwide. Importantly, HFrEF is frequently accompanied by the presence of cardiac and non-cardiac comorbidities that may greatly influence the management and prognosis of the disease. In this review article, we will focus on three important comorbidities in HFrEF; atrial fibrillation (AF), advanced renal disease, and elderly, which all have a paramount impact on progression of the disease, management strategies, and response to therapy. AF is very common in HFrEF and shares many risk factors. AF aggravates heart failure and contributes to HFrelated adverse clinical outcomes; hence it requires special consideration in HFrEF management. The kidney function is largely affected by the reduced cardiac output developed in the setting of HFrEF, and the neurohormonal feedback effects create a complex interplay that pose challenges in the management of HFrEF when renal function is significantly impaired. Cardiorenal syndrome is a challenging sequela with increased morbidity and mortality thereby reflecting the delicate and complex balance between the heart and the kidney in HFrEF and renal failure conditions. Furthermore, patients with advanced renal failure have poor prognosis in the presence of HFrEF with limited treatment options. Finally, aging and frailty are important factors that influence treatment strategies in HFrEF with greater emphasis on tolerability and safety of the various HFrEF therapies in elderly individuals

Analysis of Trends and Outcomes of 90 and 180 Day Readmissions After Left Ventricular Assist Device Implantation

Despite decreasing morbidity and mortality in left ventricular assist device (LVAD) recipients, readmission after implantation remains a major problem. Our aim was to investigate the trends and outcomes of 90 and 180 day readmission in this population. The National Readmission Database from 2012 to 2017 was queried to identify LVAD recipients. A total of 5,907 adults (90 day readmissions) and 3,653 adults (180 day readmissions) who survived LVAD implantation during the index admission were included in our analysis. Readmissions occurred in 45.6% and 65.1% by 90 and 180 days, respectively, with most readmissions occurring within the first 20 days. During the study period, mortality at index admission and readmission rate after discharge from index admission remained stable, whereas mortality during the readmission declined overtime both at 90 and 180 days. Heart failure was the most common cause for readmission (both 90 and 180 days), while its incidence also increased over the years. Among the reasons for readmission, intracranial bleeding, ischemic stroke, and device thrombosis were associated with highest mortality and gastrointestinal bleeding with the lowest. Intracranial bleeding, device thrombosis, and device infection were associated with longer length of stay. Multivariate logistic regression models identified gastrointestinal bleeding, length of stay during index admission, and end-stage renal disease requiring hemodialysis as risk factors of readmissions. Our study has unveiled several important factors associated with readmission and mortality. Approaches to identify and prevent readmissions early after LVAD implantation by addressing these factors may lead to lower morbidity, healthcare cost related to readmission, and improved quality of life

Outcomes after heart transplantation in patients with cardiac sarcoidosis

Background The number of patients with sarcoidosis requiring heart transplantation (HT) is increasing. The aim of this study was to evaluate outcomes of isolated HT in patients with sarcoid cardiomyopathy and compare them to recipients with non-ischaemic restrictive or dilated cardiomyopathy. Methods and results Adult HT recipients were identified in the UNOS Registry between 1990 and 2020. Patients were grouped according to diagnosis. The cumulative incidences for the all-cause mortality and rejection were compared using Fine and Gray model analysis, accounting for re-transplantation as a competing risk. Rejection was evaluated using logistic regression analysis. We also reviewed characteristics and outcomes of all HT recipients with previous diagnosis of sarcoid cardiomyopathy from a single centre. A total of 30 160 HT recipients were included in the present study (n = 239 sarcoidosis, n = 1411 non-ischaemic restrictive cardiomyopathy, and n = 28 510 non-ischaemic dilated cardiomyopathy). During a total of 194 733 patient-years, all-cause mortality at the latest follow-up was not significantly different when comparing sarcoidosis to non-ischaemic dilated cardiomyopathy [adjusted subhazard ratio (aSHR) 1.46, 95% confidence intervals (Cis): 0.9-2.4, P = 0.12] or restrictive cardiomyopathy (aSHR 1.12, 95% CI: 0.65-1.95, P = 0.67). Accordingly, multivariable analysis suggested that 1 year mortality was not significantly different between sarcoidosis and non-ischaemic dilated cardiomyopathy (aSHR 1.56, 95% CI: 0.9-2.7, P = 0.12) or restrictive cardiomyopathy (aSHR 1.15, 95% CI: 0.61-2.18, P = 0.66). No differences were observed regarding 30 day mortality, treated and hospitalized acute rejection, and 30 day death from graft failure after HT. Thirty-day mortality did not improve significantly in more recent HT eras whereas there was a trend towards improved 1 year mortality in the latest HT era (P = 0.06). Data from the single-centre case review showed excellent long-term outcomes with sirolimus-based immunosuppression. Conclusions Short-term and long-term post HT outcomes among patients with sarcoid cardiomyopathy are similar to those with common types of non-ischaemic cardiomyopathy