Liposome-encapsulated hemoglobin rescues hemorrhagic shock heart through anti-ischemic and anti-arrhythmogenic effects on myocardium in repetitive 65% bleeding rat model.

BACKGROUND: Phase I clinical trial of an artificial oxygen carrier (liposome-encapsulated hemoglobin vesicles [HbVs]) is safely completed, considering the other clinical application. Herein, we aimed to investigate the resuscitation effects of HbVs in cases of lethal hemorrhage, including the mechanisms involved. METHODS: Optical mapping analysis (OMP) and electrophysiological studies (EPS), immunostaining pathological examination for hypoxia-inducible factor-1α (HIF1-alpha) in the heart tissue, and blood troponin I (TnI) level measurements were performed in rats that underwent five rounds of spontaneous arterial bleeding with up to 65% hemorrhage. RESULTS: Ten rats in each group were resuscitated by a transvenous infusion of 5% albumin (ALB), washed erythrocytes (wRBC), HbVs (HbV), 50% HbV diluted by 5% albumin (50% HbV), and 66% HbV diluted by 5% albumin (66% HbV). The rats in the ALB and 50% HbV groups died, whereas those in the other groups survived. OMP showed impaired action potential duration dispersion (APDd) in the left ventricle in the ALB and 50% HbV groups, which was attenuated in the other groups. Lethal arrhythmias were provoked by EPS in the ALB and 50% HbV groups but not in the other groups. HIF1-alpha was positively stained only in the ALB and 50% HbV groups. TnI levels were elevated in the ALB and 50% HbV groups. CONCLUSIONS: Acute lethal hemorrhage causes myocardial ischemia with hypoxia and arrhythmias, which may be induced by impaired APDd and myocardial damage, reflected in the increased levels of HIF1-alpha and TnI. HbVs could be useful for resuscitation and may help save patients with injuries such as gunshot wounds.

The Safety and Efficacy of Sodium-Glucose Cotransporter-2 Inhibitors for Patients with Sarcopenia or Frailty: Double Edged Sword?

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) show cardiovascular protective effects, regardless of the patient's history of diabetes mellitus (DM). SGLT2is suppressed cardiovascular adverse events in patients with type 2 DM, and furthermore, SGLT-2is reduced the risk of worsening heart failure (HF) events or cardiovascular death in patients with HF. Along with these research findings, SGLT-2is are recommended for patients with HF in the latest guidelines. Despite these benefits, the concern surrounding the increasing risk of body weight loss and other adverse events has not yet been resolved, especially for patients with sarcopenia or frailty. The DAPA-HF and DELIVER trials consistently showed the efficacy and safety of SGLT-2i for HF patients with frailty. However, the Rockwood frailty index that derived from a cumulative deficit model was employed for frailty assessment in these trials, which might not be suitable for the evaluation of physical frailty or sarcopenia alone. There is no fixed consensus on which evaluation tool to use or its cutoff value for the diagnosis and assessment of frailty in HF patients, or which patients can receive SGLT-2i safely. In this review, we summarize the methodology of frailty assessment and discuss the efficacy and safety of SGLT-2i for HF patients with sarcopenia or frailty.

Sex Differences in Cardiac and Clinical Phenotypes and Their Relation to Outcomes in Patients with Heart Failure.

Biological sex is one of the major factors characterizing the heart failure (HF) patient phenotype. Understanding sex-related differences in HF is crucial to implement personalized care for HF patients with various phenotypes. There are sex differences in left ventricular (LV) remodeling patterns in the HF setting, namely, more likely concentric remodeling and diastolic dysfunction in women and eccentric remodeling and systolic dysfunction in men. Recently supra-normal EF (snLVEF) has been recognized as a risk of worse outcome. This pathology might be more relevant in female patients. The possible mechanism may be through coronary microvascular dysfunction and sympathetic nerve overactivation from the findings of previous studies. Further, estrogen deficit might play a significant role in this pathophysiology. The sex difference in body composition may also be related to the difference in LV remodeling and outcome. Lower implementation in guideline-directed medical therapy (GDMT) in female HFrEF patients might also be one of the factors related to sex differences in relation to outcomes. In this review, we will discuss the sex differences in cardiac and clinical phenotypes and their relation to outcomes in HF patients and further discuss how to provide appropriate treatment strategies for female patients.

ß1 Adrenergic Receptor Autoantibodies and IgG Subclasses: Current Status and Unsolved Issues.

A wide range of anti-myocardial autoantibodies have been reported since the 1970s. Among them, autoantibodies against the ß1-adrenergic receptor (ß1AR-AAb) have been the most thoroughly investigated, especially in dilated cardiomyopathy (DCM). Β1AR-Aabs have agonist effects inducing desensitization of ß1AR, cardiomyocyte apoptosis, and sustained calcium influx which lead to cardiac dysfunction and arrhythmias. Β1AR-Aab has been reported to be detected in approximately 40% of patients with DCM, and the presence of the antibody has been associated with worse clinical outcomes. The removal of anti-myocardial autoantibodies including ß1AR-AAb by immunoadsorption is beneficial for the improvement of cardiac function for DCM patients. However, several studies have suggested that its efficacy depended on the removal of AAbs belonging to the IgG3 subclass, not total IgG. IgG subclasses differ in the structure of the Fc region, suggesting that the mechanism of action of ß1AR-AAb differs depending on the IgG subclasses. Our previous clinical research demonstrated that the patients with ß1AR-AAb better responded to ß-blocker therapy, but the following studies found that its response also differed among IgG subclasses. Further studies are needed to elucidate the possible pathogenic role of IgG subclasses of ß1AR-AAbs in DCM, and the broad spectrum of cardiovascular diseases including HF with preserved ejection fraction.

Reduced reactive hyperemia of the brachial artery in diabetic patients assessed by repeated measurements: The FMD-J B study.

Type 2 diabetes mellitus (T2DM) is a major cause of microvascular dysfunction. However, its effect on blood flow patterns during ischemic demand has not been adequately elucidated. In this study, we investigated the hypothesis that microvascular dysfunction in patients with T2DM manifests as brachial reactive hyperemia (BRH), defined as the ratio of peak blood flow velocities in a brachial artery before and after forearm cuff occlusion. The study enrolled 943 subjects (men, n = 152 [T2DM] and n = 371 [non-T2DM]; women, n = 107 [T2DM] and n = 313 [non-T2DM], respectively) with no history of cardiovascular disease. Semiautomatic measurements were obtained three times at 1.5-year intervals to confirm the reproducibility of factors involved in BRH for each sex. An age-adjusted mixed model demonstrated attenuated BRH in the presence of T2DM in both men (p = 0.022) and women (p = 0.031) throughout the study period. Post hoc analysis showed that the estimated BRH was significantly attenuated in patients with T2DM regardless of sex, except at baseline in women. In multivariate regression analysis, T2DM was a negative predictor of BRH at every measurement in men. For women, BRH was more strongly associated with alcohol consumption. Repeated measurements analysis revealed that T2DM was associated with attenuated postocclusion reactive hyperemia.

Coronary microvascular dysfunction in heart failure patients.

Coronary microcirculation has multiple layers of autoregulatory function to maintain resting flow and augment hyperemic flow in response to myocardial demands. Functional or structural alterations in the coronary microvascular function are frequently observed in patients with heart failure with preserved or reduced ejection fraction, which may lead to myocardial ischemic injury and resultant worsening of clinical outcomes. In this review, we describe our current understanding of coronary microvascular dysfunction in the pathogenesis of heart failure with preserved and reduced ejection fraction.

Reactive Oxygen Species in the Aorta and Perivascular Adipose Tissue Precedes Endothelial Dysfunction in the Aorta of Mice with a High-Fat High-Sucrose Diet and Additional Factors.

Metabolic syndrome (Mets) is the major contributor to the onset of metabolic complications, such as hypertension, type 2 diabetes mellitus (DM), dyslipidemia, and non-alcoholic fatty liver disease, resulting in cardiovascular diseases. C57BL/6 mice on a high-fat and high-sucrose diet (HFHSD) are a well-established model of Mets but have minor endothelial dysfunction in isolated aortas without perivascular adipose tissue (PVAT). The purpose of this study was to evaluate the effects of additional factors such as DM, dyslipidemia, and steatohepatitis on endothelial dysfunction in aortas without PVAT. Here, we employed eight-week-old male C57BL/6 mice fed with a normal diet (ND), HFHSD, steatohepatitis choline-deficient HFHSD (HFHSD-SH), and HFHSD containing 1% cholesterol and 0.1% deoxycholic acid (HFHSD-Chol) for 16 weeks. At week 20, some HFHSD-fed mice were treated with streptozocin to develop diabetes (HFHSD-DM). In PVAT-free aortas, the endothelial-dependent relaxation (EDR) did not differ between ND and HFHSD (p = 0.25), but in aortas with PVAT, the EDR of HFHSD-fed mice was impaired compared with ND-fed mice (p = 0.005). HFHSD-DM, HFHSD-SH, and HFHSD-Chol impaired the EDR in aortas without PVAT (p < 0.001, p = 0.019, and p = 0.009 vs. ND, respectively). Furthermore, tempol rescued the EDR in those models. In the Mets model, the EDR is compromised by PVAT, but with the addition of DM, dyslipidemia, and SH, the vessels themselves may result in impaired EDR.

A Low Arginine/Ornithine Ratio is Associated with Long-Term Cardiovascular Mortality.

AIMS: The long-term prognostic value of the bioavailability of L-arginine, an important source of nitric oxide for the maintenance of vascular endothelial function, has not been investigated fully. We therefore investigated the relationship between amino acid profile and long-term prognosis in patients with a history of standby coronary angiography. METHODS: We measured the serum concentrations of L-arginine, L-citrulline, and L-ornithine by high-speed liquid chromatography. We examined the relationship between the L-arginine/L-ornithine ratio and the incidence of all-cause death, cardiovascular death, and major adverse cardiovascular events (MACEs) in 262 patients (202 men and 60 women, age 65±13 years) who underwent coronary angiography over a period of ≤ 10 years. RESULTS: During the observation period of 5.5±3.2 years, 31 (12%) patients died, including 20 (8%) of cardiovascular death, while 32 (12%) had MACEs. Cox regression analysis revealed that L-arginine/L-ornithine ratio was associated with an increased risk for all-cause death (unadjusted hazard ratio, 95% confidence interval) (0.940, 0.888-0.995) and cardiovascular death (0.895, 0.821-0.965) (p＜0.05 for all). In a model adjusted for age, sex, hypertension, hyperlipidemia, diabetes, current smoking, renal function, and log10-transformed brain natriuretic peptide level, cardiovascular death (0.911, 0.839-0.990, p=0.028) retained an association with a low L-arginine/ L-ornithine ratio. When the patients were grouped according to an L-arginine/L-ornithine ratio of 1.16, the lower L-arginine/L-ornithine ratio group had significantly higher incidence of all-cause death, cardiovascular death, and MACEs. CONCLUSION: A low L-arginine/L-ornithine ratio may be associated with increased 10-year cardiac mortality.

D-Dimer beyond Diagnosis of Pulmonary Embolism: Its Implication for Long-Term Prognosis in Cardio-Oncology Era.

Venous thromboembolism (VTE) is a common comorbidity of cancer, often referred to as cancer-associated thrombosis (CAT). Even though its prevalence has been increasing, its clinical picture has not been thoroughly investigated. In this single-center retrospective observational study, 259 patients who were treated for pulmonary embolism (PE) between January 2015 and December 2020 were available for analysis. The patients were divided by the presence or absence of concomitant malignancy, and those with malignancy (N = 120, 46%) were further classified into active (N = 40, 15%) and inactive groups according to the treatment status of malignancy. In patients with malignancy, PE was more often diagnosed incidentally by computed tomography or D-dimer testing, and the proportion of massive PE was lower. Although D-dimer levels overall decreased after the initiation of anticoagulation therapy, concomitant malignancy was independently associated with higher D-dimer at discharge despite the lower severity of PE at onset. The patients with malignancy had a poor prognosis during post-discharge follow-up. Active malignancy was independently associated with major adverse cardiovascular events (MACE) and major bleeding. D-dimer at discharge was an independent predictor of mortality even after adjustment for malignancy. This study's findings suggest that CAT-PE patients might have hypercoagulable states, which can potentially lead to a poorer prognosis.

Short-Chain Fatty Acids in Gut-Heart Axis: Their Role in the Pathology of Heart Failure.

Heart failure (HF) is a syndrome with global clinical and socioeconomic burden worldwide owing to its poor prognosis. Accumulating evidence has implicated the possible contribution of gut microbiota-derived metabolites, short-chain fatty acids (SCFAs), on the pathology of a variety of diseases. The changes of SCFA concentration were reported to be observed in various cardiovascular diseases including HF in experimental animals and humans. HF causes hypoperfusion and/or congestion in the gut, which may lead to lowered production of SCFAs, possibly through the pathological changes of the gut microenvironment including microbiota composition. Recent studies suggest that SCFAs may play a significant role in the pathology of HF, possibly through an agonistic effect on G-protein-coupled receptors, histone deacetylases (HDACs) inhibition, restoration of mitochondrial function, amelioration of cardiac inflammatory response, its utilization as an energy source, and remote effect attributable to a protective effect on the other organs. Collectively, in the pathology of HF, SCFAs might play a significant role as a key mediator in the gut-heart axis. However, these possible mechanisms have not been entirely clarified and need further investigation.

Association of serum nitric oxide metabolite level with mortality in patients undergoing coronary angiography.

BACKGROUND: Nitric oxide (NO) is a relevant molecule for vascular homeostasis. The level of serum NO metabolites (NOx), which consist of nitrite and nitrate, has been investigated as an alternative biomarker of NO production, but its clinical value has not yet been determined. METHODS AND RESULTS: 143 patients (66 ±â€¯12 years old) were followed up after coronary catheterization. During a median (inter-quartile range) observation period of 6.13 (3.32-9.21) years, there were 20 (14 %) all-cause deaths, including 11 (8 %) cardiovascular deaths, 17 (12 %) major adverse cardiovascular events, and 17 (12 %) hospital admissions for heart failure. Median NOx level was 34.5 µmol/L (23.9-54.3). NOx was a risk factor for all-cause death [hazard ratio (HR) by unit increase, 1.010, 95 % confidence interval (CI) 1.001-1.018; p = 0.021] and heart failure (HR 1.010, CI 1.001-1.019; p = 0.029). Even after adjustment for age, sex, coronary risk factors, C-reactive protein, log-transformed brain natriuretic peptide, estimated glomerular filtration rate, and nitrate treatment, NOx was a risk factor for all-cause death (HR 1.015, CI 1.004-1.027; p = 0.008) and admission with heart failure (HR 1.018, CI 1.005-1.018, p = 0.007). CONCLUSIONS: An increase in serum NOx level does not herald a benign clinical course but is an independent predictor of high risk of any-cause mortality and heart failure.

Sarco/Endoplasmic Reticulum Ca2+ ATPase 2 Activator Ameliorates Endothelial Dysfunction; Insulin Resistance in Diabetic Mice.

Background: Sarco/endoplasmic reticulum Ca2+-ATPase2 (SERCA2) is impaired in various organs in animal models of diabetes. The purpose of this study was to test the effects of an allosteric SERCA2 activator (CDN1163) on glucose intolerance, hepatosteatosis, skeletal muscle function, and endothelial dysfunction in diabetic (db/db) mice. Methods: Either CDN1163 or vehicle was injected intraperitoneally into 16-week-old male control and db/db mice for 5 consecutive days. Results: SERCA2 protein expression was decreased in the aorta of db/db mice. In isometric tension measurements of aortic rings from db/db mice treated with CDN1163, acetylcholine (ACh)-induced relaxation was improved. In vivo intraperitoneal administrations of CDN 1163 also increased ACh-induced relaxation. Moreover, CDN1163 significantly decreased blood glucose in db/db mice at 60 and 120 min during a glucose tolerance test; it also decreased serum insulin levels, hepatosteatosis, and oxygen consumption in skeletal muscle during the early period of exercise in db/db mice. Conclusions: CDN1163 directly improved aortic endothelial dysfunction in db/db mice. Moreover, CDN1163 improved hepatosteatosis, skeletal muscle function, and insulin resistance in db/db mice. The activation of SERCA2 might be a strategy for the all the tissue expressed SERCA2a improvement of endothelial dysfunction and the target for the organs related to insulin resistance.

Delayed Vasovagal Reaction with Reflex Syncope Following COVID-19 Vaccination.

Coronavirus disease 2019 (COVID-19) has become a pandemic, and vaccines remain the only effective tools available for ending it. However, their side effects, such as syncope, which mimics sudden cardiac death, are serious concerns. We herein report 6 cases of delayed vasovagal syncope and presyncope (VVR) caused by COVID-19 vaccination among 25,530 COVID-19 patients. The prevalence of delayed VVR due to COVID-19 vaccination was 0.026%. In addition, no delayed VVR was found among 17,386 patients who received the influenza vaccine. Delayed VVR is likely to be overlooked if medical staff are not aware of this symptom. This report provides significant information regarding effects of COVID-19 vaccination.

Vasospasm-induced ST-segment elevation myocardial infarction in a premenopausal woman with endothelial dysfunction.

ST-segment elevation myocardial infarction (STEMI) can be caused by coronary artery vasospasm (VSA) due to endothelial dysfunction. However, the clinical role of endothelial function tests in VSA-induced STEMI is not fully understood. We present the case of a 43-year-old woman with atypical chest pain and no coronary risk factors. STEMI caused by VSA was diagnosed. Flow-mediated vasodilatation (FMD) and EndPAT tests were performed; the FMD and reactive hyperaemia index were 3.8% and 1.23, respectively. Endothelial dysfunction is the putative cause of STEMI. FMD and EndPAT tests might be useful for predicting adverse outcomes in young premenopausal women with VSA.

Effectiveness of the d-ROMs oxidative stress test to predict long-term cardiovascular mortality.

BACKGROUND: The long-term prognostic value of the derivatives of reactive oxidative metabolites (d-ROMs) oxidative stress test, which measures hydroperoxide in blood, has not been fully investigated. METHODS AND RESULTS: We administered the d-ROMs test to 265 patients with cardiovascular disease (204 men, 61 women; age, 65 ± 13 years) and followed these patients for up to 10 years. During the observational period of 5.82 (2.47-8.34) years, 31 (12%) patients died, including 20 (8%) of cardiovascular death, and 33 (12%) had major adverse cardiovascular events (MACEs). Cox regression analysis revealed that patients with a d-ROMs value ≥395 U.CARR had a greater risk for all-cause mortality [unadjusted hazard ratio (95% confidence interval), 3.586 (1.772-7.257)], cardiovascular death [7.034 (2.805-17.640)], and MACEs [4.440 (2.237-8.814)] (p < 0.001 for all). In a model adjusted for age, sex, estimated glomerular filtration rate, C-reactive protein, diabetes, hypertension, hyperlipidemia, coronary artery diseases, current smoking, and log-transformed brain natriuretic peptide, all-cause death [2.311 (1.059-5.135), p = 0.036], cardiovascular death [4.398 (1.599-12.099), p = 0.004], MACEs [2.696 (1.266-5.739), p = 0.010] were still significant in patients with high d-ROMS values. CONCLUSION: A high d-ROMs value is an independent predictor of the long-term risk of cardiovascular mortality. A d-ROMs value of 395 U.CARR was considered to be an appropriate threshold for distinguishing prognosis.