Background Approximately 5.1 million Israelis had been fully immunized against coronavirus disease 2019 (Covid-19) after receiving two doses of the BNT162b2 messenger RNA vaccine (Pfizer–BioNTech) by May 31, 2021. After early reports of myocarditis during adverse events monitoring, the Israeli Ministry of Health initiated active surveillance. Methods We retrospectively reviewed data obtained from December 20, 2020, to May 31, 2021, regarding all cases of myocarditis and categorized the information using the Brighton Collaboration definition. We analyzed the occurrence of myocarditis by computing the risk difference for the comparison of the incidence after the first and second vaccine doses (21 days apart); by calculating the standardized incidence ratio of the observed-to-expected incidence within 21 days after the first dose and 30 days after the second dose, independent of certainty of diagnosis; and by calculating the rate ratio 30 days after the second dose as compared with unvaccinated persons. Results Among 304 persons with symptoms of myocarditis, 21 had received an alternative diagnosis. Of the remaining 283 cases, 142 occurred after receipt of the BNT162b2 vaccine; of these cases, 136 diagnoses were definitive or probable. The clinical presentation was judged to be mild in 129 recipients (95%); one fulminant case was fatal. The overall risk difference between the first and second doses was 1.76 per 100,000 persons (95% confidence interval [CI], 1.33 to 2.19), with the largest difference among male recipients between the ages of 16 and 19 years (difference, 13.73 per 100,000 persons; 95% CI, 8.11 to 19.46). As compared with the expected incidence based on historical data, the standardized incidence ratio was 5.34 (95% CI, 4.48 to 6.40) and was highest after the second dose in male recipients between the ages of 16 and 19 years (13.60; 95% CI, 9.30 to 19.20). The rate ratio 30 days after the second vaccine dose in fully vaccinated recipients, as compared with unvaccinated persons, was 2.35 (95% CI, 1.10 to 5.02); the rate ratio was again highest in male recipients between the ages of 16 and 19 years (8.96; 95% CI, 4.50 to 17.83), with a ratio of 1 in 6637. Conclusions The incidence of myocarditis, although low, increased after the receipt of the BNT162b2 vaccine, particularly after the second dose among young male recipients. The clinical presentation of myocarditis after vaccination was usually mild.

Haptoglobin is an abundant hemoglobin-binding protein present in the plasma. The function of haptoglobin is primarily to determine the fate of hemoglobin released from red blood cells after either intravascular or extravascular hemolysis. There are two common alleles at the Hp genetic locus denoted 1 and 2. There are functional differences between the Hp 1 and Hp 2 protein products in protecting against hemoglobin-driven oxidative stress that appear to have important clinical significance. In particular, individuals with the Hp 2-2 genotype and diabetes mellitus appear to be at significantly higher risk of microvascular and macrovascular complications. A pharmacogenomic strategy of administering high dose antioxidants specifically to Hp 2-2 DM individuals may be clinically effective.

Abstract-A major function of haptoglobin (Hp) is to bind hemoglobin (Hb) to form a stable Hp-Hb complex and thereby prevent Hb-induced oxidative tissue damage. Clearance of the Hp-Hb complex can be mediated by the monocyte/macrophage scavenger receptor CD163. We recently demonstrated that diabetic individuals homozygous for the Hp 2 allele (Hp 2-2) were at 500% greater risk of cardiovascular disease (CVD) compared with diabetic individuals homozygous for the Hp 1 allele (Hp 1-1). No differences in risk by Hp type were seen in individuals without diabetes. To understand the relationship between the Hp polymorphism and diabetic CVD, we sought to identify differences in antioxidant and scavenging functions between the Hp types and to determine how these functions were modified in diabetes. The scavenging function of Hp was assessed using rhodamine-tagged and 125 I-Hp in cell lines stably transfected with CD163 and in macrophages expressing endogenous CD163. We found that the rate of clearance of Hp 1-1-Hb by CD163 is markedly greater than that of Hp 2-2-Hb. Diabetes is associated with an increase in the nonenzymatic glycosylation of serum proteins, including Hb. The antioxidant function of Hp was assessed with glycosylated and nonglycosylated Hb. We identified a severe impairment in the ability of Hp to prevent oxidation mediated by glycosylated Hb. We propose that the specific interaction between diabetes, CVD, and Hp genotype is the result of the heightened urgency of rapidly clearing glycosylated Hb-Hp complexes from the subendothelial space before they can oxidatively modify low-density lipoprotein to atherogenic oxidized low-density lipoprotein.

Abstract-We have recently demonstrated in multiple independent population-based longitudinal and cross sectional analyses that the haptoglobin 2-2 genotype is associated with an increased risk for diabetic cardiovascular disease. The chief function of haptoglobin (Hp) is to bind to hemoglobin and thereby prevent hemoglobin-induced oxidative tissue damage. This antioxidant function of haptoglobin is mediated in part by the ability of haptoglobin to prevent the release of iron from hemoglobin on its binding. We hypothesized that there may be diabetes-and haptoglobin genotypedependent differences in the amount of catalytically active redox active iron derived from hemoglobin. We tested this hypothesis using several complementary approaches both in vitro and in vivo. First, measuring redox active iron associated with haptoglobin-hemoglobin complexes in vitro, we demonstrate a marked increase in redox active iron associated with Hp 2-2-glycohemoglobin complexes. Second, we demonstrate increased oxidative stress in tissue culture cells exposed to haptoglobin 2-2-hemoglobin complexes as opposed to haptoglobin 1-1-hemoglobin complexes, which is inhibitable by desferrioxamine by either a chelation or reduction mechanism. Third, we demonstrate marked diabetes-dependent differences in the amount of redox active iron present in the plasma of mice genetically modified expressing the Hp 2 allele as compared with the Hp 1 allele. Taken together these data implicate redox active iron in the increased susceptibility of individuals with the Hp 2 allele to diabetic vascular disease. Key Words: diabetes Ⅲ oxidative stress Ⅲ iron Ⅲ haptoglobin Ⅲ hemoglobin T he haptoglobin (Hp) gene locus on chromosome 16q22 is polymorphic with two common alleles existing in man, denoted 1 and 2. 1 We have recently established in multiple independent population-based longitudinal and cross sectional studies that the haptoglobin genotype is an independent risk factor for diabetic cardiovascular disease. 2-6 Specifically, we have demonstrated that diabetic individuals homozygous for the haptoglobin 2 allele (Hp 2-2) are at significantly greater risk of developing cardiovascular disease as compared with diabetic individuals homozygous for the haptoglobin 1 allele (Hp 1-1) with an intermediate risk being found in the heterozygote. 3 Haptoglobin is an antioxidant as a direct result of its ability to prevent hemoglobin-driven oxidation. 7 The stoichiometric binding of haptoglobin to hemoglobin not only stabilizes the heme iron moiety in hemoglobin (Hb) 8 but also promotes its scavenging by the CD163 macrophage receptor by receptormediated endocytosis. 9 We have recently demonstrated that the ability of haptoglobin to protect against hemoglobindriven oxidative injury is abrogated when hemoglobin becomes glycated, a process that is markedly accelerated in the diabetic state. 10 Glycohemoglobin-haptoglobin complexes are catalytically redox active and therefore the rate at which haptoglobin-hemoglobin complexes are cleared from the serum and extravascular ...

OBJECTIVE-Pharmacogenomics is a key component of personalized medicine. The Israel Cardiovascular Events Reduction with Vitamin E Study, a prospective placebo-controlled study, recently demonstrated that vitamin E could dramatically reduce CVD in individuals with diabetes and the haptoglobin (Hp) 2-2 genotype (40% of diabetic individuals). However, because of the large number of clinical trials that failed to demonstrate benefit from vitamin E coupled with the lack of a mechanistic explanation for why vitamin E should be beneficial only in diabetic individuals with the Hp 2-2 genotype, enthusiasm for this pharmacogenomic paradigm has been limited. In this study, we sought to provide such a mechanistic explanation based on the hypothesis that the Hp 2-2 genotype and diabetes interact to promote HDL oxidative modification and dysfunction.RESEARCH DESIGN AND METHODS-Hb and lipid peroxides were assessed in HDL isolated from diabetic individuals or mice with the Hp 1-1 or Hp 2-2 genotypes. HDL function was assessed based on its ability to promote cholesterol efflux from macrophages. A crossover placebo-controlled study in Hp 2-2 diabetic humans and in Hp 1-1 and Hp 2-2 diabetic mice assessed the ability of vitamin E to favorably modify these structural and functional parameters.RESULTS-Hb and lipid peroxides associated with HDL were increased and HDL function was impaired in Hp 2-2 diabetic individuals and mice. Vitamin E decreased oxidative modification of HDL and improved HDL function in Hp 2-2 diabetes but had no effect in Hp 1-1 diabetes.CONCLUSIONS-Vitamin E significantly improves the quality of HDL in Hp 2-2 diabetic individuals.

Abstract-In individuals with diabetes mellitus (DM), the haptoglobin (Hp) genotype is a major determinant of susceptibility to myocardial infarction. We have proposed that this is because of DM and Hp genotype-dependent differences in the response to intraplaque hemorrhage. The macrophage hemoglobin scavenging receptor CD163 plays an essential role in the clearance of hemoglobin released from lysed red blood cells after intraplaque hemorrhage. We sought to test the hypothesis that expression of CD163 is DM and Hp genotype-dependent. CD163 was quantified in plaques by immunohistochemistry, on peripheral blood monocytes (PBMs) by FACS, and as soluble CD163 (sCD163 iabetes mellitus (DM) atherosclerosis is characterized by increased neovascularization and blood vessel fragility resulting in increased microhemorrhages and extravasation of erythrocytes, and the consequent release of extracorpuscular "free" hemoglobin (Hb) into the atherosclerotic plaque.

Aims Individuals with both diabetes mellitus (DM) and the Haptoglobin (Hp) 2-2 genotype are at increased risk of cardiovascular disease. As the antioxidant function of the Hp 2-2 protein is impaired, we sought to test the pharmacogenomic hypothesis that antioxidant vitamin E supplementation would provide cardiovascular protection to Hp 2-2 DM individuals. Materials & methods We determined the Hp genotype on DM participants from two trials (HOPE and ICARE) and assessed the effect of vitamin E by Hp genotype on their common prespecified outcome, the composite of stroke, myocardial infarction and cardiovascular death. Data was analyzed with a fixed-effect model. These results were input into a simulation model, the Evidence Based Medicine Integrator, in order to estimate their long-term implications in a real-world population from Kaiser Permanente (CA, USA). Results Meta-analysis of the two trials demonstrated a significant overall reduction in the composite end point in Hp 2-2 DM individuals with vitamin E (odds ratio: 0.58; 95% CI: 0.40–0.86; p = 0.006). There was a statistically significant interaction between the Hp genotype and vitamin E on the composite end point. In these trials, Hp typing of 69 DM individuals and treating those with the Hp 2-2 with vitamin E prevented one myocardial infarct, stroke or cardiovascular death. Lifelong administration of vitamin E to Hp 2-2 DM individuals in the Kaiser population would increase their life expectancy by 3 years. Conclusion A pharmacogenomic strategy of screening DM individuals for the Hp genotype and treating those with Hp 2-2 with vitamin E appears to be highly clinically effective.

Patients with diabetes presenting with acute myocardial infarction (AMI) have an increased rate of death and heart failure. Patients with diabetes homozygous for the haptoglobin (Hp) 1 allele (Hp 1-1) develop fewer vascular complications. We tested the hypothesis that Hp type is related to the outcome of patients with diabetes presenting with AMI. We prospectively assessed the relationship between Hp type and 30-day mortality and heart failure in 1,437 patients with AMI (506 with diabetes). Multivariate logistic regression identified a significant interaction between Hp type and diabetes status on these outcome measures. Hp type was not related to outcome among patients without diabetes. In contrast, Hp 1-1 was associated with a strong protective effect with regard to the primary end point of death (OR 0.14, P ‫؍‬ 0.015) and for death and heart failure (OR 0.35; 95% CI 0.15-0.86, P ‫؍‬ 0.018) among patients with diabetes. Finally, among patients with diabetes, Hp 1-1 was associated with smaller infarct size. This study demonstrates that in patients with diabetes and AMI, the Hp type is an important determinant of clinical outcome and infarct size. Diabetes 54:2802-2806, 2005 P atients with diabetes presenting with acute myocardial infarction (AMI) have a poor in-hospital and long-term prognosis (1). The excess in-hospital mortality and morbidity correlates primarily with an increased incidence of congestive heart failure (1,2), with heart failure developing at about twice the rate in patients with diabetes than in patients without diabetes(1). Diabetes is also a risk factor for cardiogenic shock in the setting of acute ischemic syndromes (3).The susceptibility to diabetic complications is partially controlled by complex unknown genetic factors (4,5). One such genetic factor appears to be a functional allelic polymorphism in the haptoglobin (Hp) gene (6 -11). In humans, there are two major alleles, denoted 1 and 2, for the Hp gene (12,13). We have recently shown that patients who are homozygous for the Hp 1 allele (Hp 1-1) are at a lower risk of developing both microvascular (6,7,10) and macrovascular complications associated with diabetes (8,9,14). We have proposed that susceptibility to diabetic vascular disease conferred by the Hp type is the result of marked differences in the antioxidant protection against hemoglobin-induced oxidation provided by the Hp 1 and Hp 2 allelic protein products (15-17). Specifically, we have shown in vitro and in vivo in mice genetically modified at the Hp locus that the Hp 1 and Hp 2 protein products differ in a diabetes-dependent fashion in their ability to prevent the release of redox active iron from hemoglobin and in the rate at which the hemoglobin-Hp complex is cleared via the CD163 scavenger receptor on monocyte/macrophages (15)(16)(17).In the present study, we sought to prospectively test the hypothesis that Hp type is related to the outcome of patients presenting with AMI. Because previous studies have shown that the effect of Hp type might be especially important in pat...