Myocardial Injury by COVID-19 Infection Assessed by Cardiovascular Magnetic Resonance Imaging　- A Prospective Multicenter Study.

BACKGROUND: This prospective multicenter study assessed the prevalence of myocardial injury in patients with COVID-19 using cardiac magnetic resonance imaging (CMR).Methods and Results: We prospectively screened 505 patients with moderate to severe COVID-19 disease from 7 hospitals in Japan. Of these patients, 31 (mean [±SD] age 63.5±10.4 years, 23 [74%] male) suspected of myocardial injury, based on elevated serum troponin or B-type natriuretic peptide concentrations either upon admission or 3 months after discharge, underwent CMR 3 months after discharge. The primary endpoint was the presence of myocardial injury, defined by any of the following: (1) contrast enhancement in the left or right ventricle myocardium on late gadolinium enhancement CMR; (2) left or right ventricular dysfunction (defined as <50% and <45%, respectively); and (3) pericardial thickening on contrast enhancement. The mean (±SD) duration between diagnosis and CMR was 117±16 days. The primary endpoint was observed in 13 of 31 individuals (42%), with 8 (26%) satisfying the modified Lake Louise Criteria for the diagnosis of acute myocarditis. CONCLUSIONS: This study revealed a high incidence of myocardial injury identified by CMR in patients with moderate to severe COVID-19 and abnormal findings for cardiac biomarkers.

MRP1-Dependent Extracellular Release of Glutathione Induces Cardiomyocyte Ferroptosis After Ischemia-Reperfusion.

BACKGROUND: The membrane components of cardiomyocytes are rich in polyunsaturated fatty acids, which are easily oxidized. Thus, an efficient glutathione-based lipid redox system is essential for maintaining cellular functions. However, the relationship between disruption of the redox system during ischemia-reperfusion (IR), oxidized lipid production, and consequent cell death (ferroptosis) remains unclear. We investigated the mechanisms underlying the disruption of the glutathione-mediated reduction system related to ferroptosis during IR and developed intervention strategies to suppress ferroptosis. METHODS: In vivo fluctuations of both intra- and extracellular metabolite levels during IR were explored via microdialysis and tissue metabolome analysis. Oxidized phosphatidylcholines were assessed using liquid chromatography high-resolution mass spectrometry. The areas at risk following IR were assessed using triphenyl-tetrazolium chloride/Evans blue stain. RESULTS: Metabolomic analysis combined with microdialysis revealed a significant release of glutathione from the ischemic region into extracellular spaces during ischemia and after reperfusion. The release of glutathione into extracellular spaces and a concomitant decrease in intracellular glutathione concentrations were also observed during anoxia-reperfusion in an in vitro cardiomyocyte model. This extracellular glutathione release was prevented by chemical inhibition or genetic suppression of glutathione transporters, mainly MRP1 (multidrug resistance protein 1). Treatment with MRP1 inhibitor reduced the intracellular reactive oxygen species levels and lipid peroxidation, thereby inhibiting cell death. Subsequent in vivo evaluation of endogenously oxidized phospholipids following IR demonstrated the involvement of ferroptosis, as levels of multiple oxidized phosphatidylcholines were significantly elevated in the ischemic region 12 hours after reperfusion. Inhibition of the MRP1 transporter also alleviated intracellular glutathione depletion in vivo and significantly reduced the generation of oxidized phosphatidylcholines. Administration of MRP1 inhibitors significantly attenuated infarct size after IR injury. CONCLUSIONS: Glutathione was released continuously during IR, primarily in an MRP1-dependent manner, and induced ferroptosis. Suppression of glutathione release attenuated ferroptosis and reduced myocardial infarct size following IR.

Perspectives of hospitalized heart failure patients: preferred and perceived participation roles in treatment decisions.

Shared decision-making (SDM) is a pivotal process in seeking optimal individual treatment and incorporating clinical evidence and patients' autonomous preferences. However, patients' actual attitudes toward participation in decision-making for state-of-the-art heart failure (HF) treatment remain unclear. We conducted a questionnaire-based survey distributed by nurses and physicians specializing in HF care to assess patients' preferred and perceived participation roles in treatment decision-making during the index hospitalization, rated on five scales (from extremely passive to purely autonomous attitudes). Simultaneously, we investigated the important factors underlying treatment decision-making from the perspective of hospitalized HF patients. Of the 202 patients who were approached by our multidisciplinary HF team between 2017 and 2020, 166 (82.2%) completed the survey. Logistic regression analyses were conducted to identify the clinical determinants of patients who reported that they left all decisions to physicians (i.e., extremely passive attitude). Of the 166 participants (male 67.5%, median age 73 years), 32.5% preferred an extremely passive attitude, while 61.4% reported that they actually chose an extremely passive attitude. A sole determinant of choosing an extremely passive decision-making role was lower educational status (odds ratio: 2.11, 95% confidence interval 1.11-4.00). The most important factor underlying the decision-making was "Physician recommendation" (89.2%). Notably, less than 50% considered "In alignment with my values and preferences" as an important factor underlying treatment decision-making. The majority of HF patients reported that they chose an extremely passive approach, and patients prioritized physician recommendation over their own values and preferences.

Confidence in self-care after heart failure hospitalization.

BACKGROUND: Understanding patient perspectives of self-care is critical for improving multidisciplinary education programs and adherence to such programs. However, perspectives of self-care for patients with heart failure (HF) as well as the association between patient perspectives and patient-physician communication remain unclear. METHODS: Confidence levels regarding self-care behaviors (eight lifestyle behaviors and four consulting behaviors) and self-monitoring were assessed using a self-administered questionnaire survey, which was directly distributed by dedicated physicians and nurses to consecutive patients hospitalized with HF in a tertiary-level hospital. Patient-physician communication was evaluated according to the quality of physician-provided information regarding "treatment and treatment choices" and "prognosis" using the Prognosis and Treatment Perception Questionnaire. Out of 202 patients, 187 (92.6 %) agreed to participate, and 176 completed the survey [valid response rate, 87.1 %; male, 67.0 %; median age, 73 (63-81) years]. Multivariate logistic regression analyses were conducted to predict low confidence in self-care (score in the lowest quartile). RESULTS: High confidence (confident or completely confident >75 % of patients) was observed for all self-care behavior categories except low-salt diet (63.1 %), regular exercise (63.1 %), and flu vaccination (65.9 %). Lower confidence in self-care behavior was associated with low quality of patient-physician communication. With regard to self-monitoring, 62.5 % of patients were not confident in distinguishing worsening symptoms of HF from other diseases; non-confidence was also associated with low quality of patient-physician communication. CONCLUSIONS: Hospitalized patients with HF had low confidence regarding regular exercise, salt restriction, and flu vaccination. The results also suggest patient-physician communication affects patient confidence.

Social Isolation and Implementation of Advanced Care Planning Among Hospitalized Patients With Heart Failure.

Background The implementation of advance care planning (ACP) in heart failure management is insufficient. Social isolation (SI) could be a barrier to ACP initiation, albeit the relationship between SI and patients' preference for ACP or end-of-life care remains unknown. Methods and Results We conducted a questionnaire survey, including assessments of SI using the 6-item Lubben Social Network Scale as well as patients' perspectives on ACP and end-of-life care. Of the 160 patients approached by our multidisciplinary heart failure team during admission, 120 patients (75.0%) completed the survey (median age, 73.0 years; men, 74.2%). A Cox proportional hazard model was constructed to elucidate the short-term (180-day) prognostic impact of SI. Overall, 28.3% of participants were at high risk for SI (6-item Lubben Social Network Scale score <12). High-risk patients had more negative attitudes toward ACP than those without (61.8% versus 80.2%; P=0.035). The actual performance of ACP conversation in patients with and without high risk were 20.6% and 30.2%, respectively. Regarding preference in end-of-life care, "Saying what one wants to tell loved ones" (73.5% versus 90.6%; P=0.016) and "Spending enough time with family" (58.8% versus 77.9%; P=0.035) were less important in high-risk patients. High risk for SI was associated with higher 180-day risk-adjusted all-cause mortality (hazard ratio, 7.89 [95% CI, 1.53-40.75]). Conclusions In hospitalized patients with heart failure, high risk for SI was frequently observed. High-risk patients were associated with a negative attitude toward ACP, despite higher mortality. Further research is required to establish an ideal approach to provide ACP in socially vulnerable patients.

Molecular Mechanism of Pathogenesis and Treatment Strategies for AL Amyloidosis.

In amyloid light-chain (AL) amyloidosis, small B-cell clones (mostly plasma cell clones) present in the bone marrow proliferate and secrete unstable monoclonal free light chains (FLCs), which form amyloid fibrils that deposit in the interstitial tissue, resulting in organ injury and dysfunction. AL amyloidosis progresses much faster than other types of amyloidosis, with a slight delay in diagnosis leading to a marked exacerbation of cardiomyopathy. In some cases, the resulting heart failure is so severe that chemotherapy cannot be administered, and death sometimes occurs within a few months. To date, many clinical studies have focused on therapeutics, especially chemotherapy, to treat this disease. Because it is necessary to promptly lower FLC, the causative protein of amyloid, to achieve a hematological response, various anticancer agents targeting neoplastic plasma cells are used for the treatment of this disease. In addition, many basic studies using human specimens to elucidate the pathophysiology of AL have been conducted. Gene mutations associated with AL, the characteristics of amyloidogenic LC, and the structural specificity of amyloid fibrils have been clarified. Regarding the mechanism of cellular and tissue damage, the mass effect due to amyloid deposition, as well as the toxicity of pre-fibrillar LC, is gradually being elucidated. This review outlines the pathogenesis and treatment strategies for AL amyloidosis with respect to its molecular mechanisms.

Treatment of transthyretin His88Arg amyloidosis with RNA interference therapy: A case report.

A new class of medicines called small interfering RNA molecule has demonstrated beneficial effects in patients with amyloidosis associated with mutations in transthyretin genes (ATTRv), but therapeutic effects towards His88Arg mutation were unknown. Here, we present two challenging cases of patisiran treatment for His88Arg variant. The first case is a 50-year-old male patient diagnosed with transthyretin amyloidosis cardiomyopathy with His88Arg mutation. Administration of patisiran 0.3 mg/kg every three weeks did not show any change in his symptoms. Echocardiography performed 1-year after drug initiation revealed progression of LV hypertrophy and systolic dysfunction with increased pleural effusion. The second case was a 63-year-old woman with heart failure (HF) caused by ATTRv cardiomyopathy with a His88Arg mutation. The patient began patisiran treatment 0.3 mg/kg every three weeks. Eleven months after beginning patisiran, her HF signs worsened with exacerbation of lung congestion and pleural effusion, resulting in hospitalization for decompensated HF. The two cases showed that treatment with patisiran for the patients with advanced stage of His88Arg ATTRv cardiomyopathy was unable to stop the progression of HF. Since the therapeutic response for each variant in ATTRv cardiomyopathy is unknown, further assessment of clinical efficacy for each individual variant is needed. .

Elderly aortic stenosis patients' perspectives on treatment goals in transcatheter aortic valvular replacement.

AIMS: Transcatheter aortic valvular replacement (TAVR) is increasingly being performed for elderly patients with aortic stenosis (AS), and current guidelines acknowledge the importance of shared decision-making in their management. This study aimed to evaluate elderly symptomatic severe AS patients' perspectives on their treatment goals and identify factors that influence their treatment choice. METHODS AND RESULTS: We performed a pre-procedural cross-sectional survey using a questionnaire at a single university hospital. The questionnaire included three primary domains: (i) symptom burden, (ii) goals and important factors related to treatment, and (iii) preferred place of residence after treatment. We investigated 98 symptomatic severe AS patients who underwent TAVR (median age 86 years, 26% men). None of the patients died during hospitalization, and most of them (94%) were discharged home. Prior to TAVR, the three most common symptom burdens were poor mobility (52%), shortness of breath (52%), and weakness (44%). The reported preferred treatment goals were symptom burden reduction (78%), independence maintenance (68%), ability to perform a specific activity/hobby (62%), and improvement in prognosis (58%). In total, 54% of the patients rated 'in alignment with my values' as the factor that affected their decision to undergo TAVR. Nearly all patients (95%) stated that they preferred to live at home after TAVR. CONCLUSIONS: Among elderly AS patients with varying symptoms who underwent TAVR, symptom burden reduction was the most cited patient-reported goal. Nearly all the patients preferred to live at home after the procedure. Encouraging patients to define their specific goals may improve the quality of shared decision-making in such settings.

Omega-3 fatty acid epoxides produced by PAF-AH2 in mast cells regulate pulmonary vascular remodeling.

Pulmonary hypertension is a fatal rare disease that causes right heart failure by elevated pulmonary arterial resistance. There is an unmet medical need for the development of therapeutics focusing on the pulmonary vascular remodeling. Bioactive lipids produced by perivascular inflammatory cells might modulate the vascular remodeling. Here, we show that ω-3 fatty acid-derived epoxides (ω-3 epoxides) released from mast cells by PAF-AH2, an oxidized phospholipid-selective phospholipase A2, negatively regulate pulmonary hypertension. Genetic deletion of Pafah2 in mice accelerate vascular remodeling, resulting in exacerbation of hypoxic pulmonary hypertension. Treatment with ω-3 epoxides suppresses the lung fibroblast activation by inhibiting TGF-ß signaling. In vivo ω-3 epoxides supplementation attenuates the progression of pulmonary hypertension in several animal models. Furthermore, whole-exome sequencing for patients with pulmonary arterial hypertension identifies two candidate pathogenic variants of Pafah2. Our findings support that the PAF-AH2-ω-3 epoxide production axis could be a promising therapeutic target for pulmonary hypertension.

H2 Inhibits the Formation of Neutrophil Extracellular Traps.

Neutrophil extracellular traps (NETs) contribute to inflammatory pathogenesis in numerous conditions, including infectious and cardiovascular diseases, and have attracted attention as potential therapeutic targets. H2 acts as an antioxidant and has been clinically and experimentally proven to ameliorate inflammation. This study was performed to investigate whether H2 could inhibit NET formation and excessive neutrophil activation. Neutrophils isolated from the blood of healthy volunteers were stimulated with phorbol-12-myristate-13-acetate (PMA) or the calcium ionophore A23187 in H2-exposed or control media. Compared with control neutrophils, PMA- or A23187-stimulated human neutrophils exposed to H2 exhibited reduced neutrophil aggregation, citrullination of histones, membrane disruption by chromatin complexes, and release of NET components. CXCR4high neutrophils are highly prone to NETs, and H2 suppressed Ser-139 phosphorylation in H2AX, a marker of DNA damage, thereby suppressing the induction of CXCR4 expression. H2 suppressed both myeloperoxidase chlorination activity and production of reactive oxygen species to the same degree as N-acetylcysteine and ascorbic acid, while showing a more potent ability to inhibit NET formation than these antioxidants do in PMA-stimulated neutrophils. Although A23187 formed NETs in a reactive oxygen species-independent manner, H2 inhibited A23187-induced NET formation, probably via direct inhibition of peptidyl arginine deiminase 4-mediated histone citrullination. Inhalation of H2 inhibited the formation and release of NET components in the blood and bronchoalveolar lavage fluid in animal models of lipopolysaccharide-induced sepsis (mice and aged mini pigs). Thus, H2 therapy can be a novel therapeutic strategy for NETs associated with excessive neutrophil activation.

Qualitative and Quantitative Effects of Fatty Acids Involved in Heart Diseases.

Fatty acids (FAs) have structural and functional diversity. FAs in the heart are closely associated with cardiac function, and their qualitative or quantitative abnormalities lead to the onset and progression of cardiac disease. FAs are important as an energy substrate for the heart, but when in excess, they exhibit cardio-lipotoxicity that causes cardiac dysfunction or heart failure with preserved ejection fraction. FAs also play a role as part of phospholipids that compose cell membranes, and the changes in mitochondrial phospholipid cardiolipin and the FA composition of plasma membrane phospholipids affect cardiomyocyte survival. In addition, FA metabolites exert a wide variety of bioactivities in the heart as lipid mediators. Recent advances in measurement using mass spectrometry have identified trace amounts of n-3 polyunsaturated fatty acids (PUFAs)-derived bioactive metabolites associated with heart disease. n-3 PUFAs have a variety of cardioprotective effects and have been shown in clinical trials to be effective in cardiovascular diseases, including heart failure. This review outlines the contributions of FAs to cardiac function and pathogenesis of heart diseases from the perspective of three major roles and proposes therapeutic applications and new medical perspectives of FAs represented by n-3 PUFAs.

Three patients of transthyretin amyloidosis in a Japanese family with amyloidogenic transthyretin Thr49Ser (p.Thr69Ser) variant.

Transthyretin (TTR)-related hereditary amyloidosis (ATTRv) is a rare autosomal dominant disorder that is caused by pathogenic missense mutation of the TTR gene. As of today, more than 150 TTR gene variants have been reported to occur as causal mutations. Herein, we present three familial patients of ATTRv caused by the Thr49Ser (p.Thr69Ser) variant, including their phenotypes and penetrance. The first patient was a 68-year-old woman with a history of carpal tunnel syndrome, who was referred to our department with heart failure symptoms. Echocardiography, 99mTechnetium (Tc)-pyrophosphate scintigraphy, and myocardial biopsy confirmed her diagnosis as TTR-related amyloidosis. Genetic testing for the TTR gene was performed, which confirmed the presence of a Thr49Ser (p.Thr69Ser) variant. The second patient, a 45-year-old woman, who was the niece of the first patient, presented with dyspnea on exertion. Her clinical manifestations included cardiac symptoms in addition to polyneuropathy. Similarly, myocardial biopsy showed TTR amyloid deposition within cardiac tissues, and TTR gene sequencing detected the presence of a Thr49Ser (p.Thr69Ser) variant. The final patient was a 42-year-old man, who was the nephew of the first patient, presented with numbness in his hands. Abdominal wall fat pad biopsy showed TTR amyloid deposition, and TTR gene sequencing was performed considering the familial history to confirm the presence of Thr49Ser (p.Thr69Ser) variant. No cardiac symptoms or dysfunctions have been observed yet, but imaging has detected TTR amyloid deposition in the heart. The present three patients with Thr49Ser (p.Thr69Ser) variant showed variation in phenotypes including cardiac and neurological manifestations at a fairly young age. In addition, the familial relationship in this report suggested that this variant is highly penetrant. Early genetic diagnosis due to collecting the genetic information from family medical history may be beneficial to improve patient prognosis via early therapeutic intervention.

Therapeutic Targets for DOX-Induced Cardiomyopathy: Role of Apoptosis vs. Ferroptosis.

Doxorubicin (DOX) is the most widely used anthracycline anticancer agent; however, its cardiotoxicity limits its clinical efficacy. Numerous studies have elucidated the mechanisms underlying DOX-induced cardiotoxicity, wherein apoptosis has been reported as the most common final step leading to cardiomyocyte death. However, in the past two years, the involvement of ferroptosis, a novel programmed cell death, has been proposed. The purpose of this review is to summarize the historical background that led to each form of cell death, focusing on DOX-induced cardiotoxicity and the molecular mechanisms that trigger each form of cell death. Furthermore, based on this understanding, possible therapeutic strategies to prevent DOX cardiotoxicity are outlined. DNA damage, oxidative stress, intracellular signaling, transcription factors, epigenetic regulators, autophagy, and metabolic inflammation are important factors in the molecular mechanisms of DOX-induced cardiomyocyte apoptosis. Conversely, the accumulation of lipid peroxides, iron ion accumulation, and decreased expression of glutathione and glutathione peroxidase 4 are important in ferroptosis. In both cascades, the mitochondria are an important site of DOX cardiotoxicity. The last part of this review focuses on the significance of the disruption of mitochondrial homeostasis in DOX cardiotoxicity.

Sex differences in sleep and psychological disturbances among patients admitted for cardiovascular diseases.

BACKGROUND: Understanding sex differences is critical for improving outcomes in patients with cardiovascular conditions. Sleep and psychological disturbances contribute to the development and progression of cardiovascular diseases, and important sex differences persist in their incidence and association with clinical outcomes. METHODS: Sex-based variation in sleep and psychological disturbances were assessed in consecutive patients with cardiovascular diseases in a single university hospital. The prevalence of insomnia, sleep disordered breathing (SDB), anxiety, and depression was assessed using the Pittsburgh Sleep Quality Index (PSQI), nocturnal pulse oximeter, and the Hospital Anxiety and Depression Scale (HADS). The effect of sex on the prevalence of sleep and psychological disturbances as well as their associations was quantified using multivariate logistic regression models. RESULTS: Among 1,233 patients (mean age 63.6 years, 25% women), women were significantly less likely than men to experience SDB (17.5% vs 31.5%, p < 0.001), but more likely to report an increased burden of insomnia (54.7% vs 43.3%, p = 0.001) and depression (23.9% vs 16.7%, p = 0.004). Insomnia was associated with depression, which was more remarkable among women (p value for interaction: 0.039). SDB was associated with anxiety among women but not men (p value for interaction: 0.003). There was no significant difference in the prevalence of anxiety between women and men. CONCLUSIONS: Among patients with cardiovascular disease, women reported an increased burden of insomnia and depression compared to men. The association between sleep and psychological disturbances may be more pronounced in women, suggesting that cardiologists should increase efforts for identification of such comorbidities and administer corresponding treatment, especially in women.

Step-by-step typing for the accurate diagnosis of concurrent light chain and transthyretin cardiac amyloidosis.

While 99m Tc-pyrophosphate scintigraphy is clearly useful in diagnosing transthyretin amyloid cardiomyopathy (ATTR-CM), it is necessary to know the pitfalls of this test for proper use. We present a rare case of concurrent ATTR-CM and amyloid light chain (AL) cardiomyopathy. The patient showed congestive heart failure with left ventricular hypertrophy. 99m Tc-pyrophosphate scintigraphy revealed abnormal cardiac uptake of Grade 3, a typical feature for ATTR-CM. However, the patient showed renal impairment with proteinuria and the presence of monoclonal gammopathy, which rather suggested AL amyloidosis. Endomyocardial biopsy, immunohistochemistry, and proteomic analysis by laser microdissection with liquid chromatography-coupled tandem mass spectrometry were performed, which finally confirmed both ATTR-CM and AL cardiomyopathy. This case implicates the importance of combining examinations and precisely interpreting the results to diagnose cardiac amyloidosis accurately.

Pharmacokinetics of hydrogen after ingesting a hydrogen-rich solution: A study in pigs.

Drinking hydrogen (H2)-rich water is a common way to consume H2. Although many studies have shown efficacy of drinking H2-rich water in neuropsychiatric and endocrine metabolic disorders, their authenticity has been questioned because none examined the associated pharmacokinetics of H2. Therefore, we performed the first study to investigate the pharmacokinetics of H2 in pigs given an H2-rich glucose solution with the aim to extrapolate the findings to humans. We inserted blood collection catheters into the jejunal and portal veins, suprahepatic inferior vena cava, and carotid artery of 4 female pigs aged 8 weeks. Then, within 2 min we infused 500 ml of either H2-rich or H2-free glucose solution into the jejunum via a percutaneous gastrostomy tube and measured changes in H2 concentration in venous and arterial blood over 120 min. After infusion of the H2-rich glucose solution, H2 concentration in the portal vein peaked at 0.05 mg/L and remained at more than 0.016 mg/L (H2 saturation level, 1%) after 1 h; it also increased after infusion of H2-free glucose solution but remained below 0.001 mg/L (H2 saturation level, 0.06%). We assume that H2 was subsequently metabolized in the liver or eliminated via the lungs because it was not detected in the carotid artery. In conclusion, drinking highly concentrated H2-rich solution within a short time is a good way to increase H2 concentration in portal blood and supply H2 to the liver.

Preferences on advance care planning and end-of-life care in patients hospitalized for heart failure.

AIMS: Early engagement in advance care planning (ACP) is recommended in heart failure (HF) management. We investigated the preferences of patients with HF regarding ACP and end-of-life (EOL) care, including their desired timing of ACP initiation. METHODS AND RESULTS: Data were collected using a 92-item questionnaire survey, which was directly distributed to hospitalized patients by dedicated physicians and nurses in a university hospital setting. One-hundred eighty-seven patients agreed to participate (response rate: 92.6%), and 171 completed the survey [valid response rate: 84.7%; men: 67.3%; median age: 73.0 (63.0-81.0) years]. Logistic regression analyses were conducted to identify the predictors of positive attitudes towards ACP. Most recognized ACP as important for their care (n = 127, 74.3%), 48.1% stated that ACP should be initiated after repeated HF hospitalizations in the past year, and 29.0% preferred ACP to begin during the first or second HF hospitalization. Only 21.7% of patients had previously engaged in ACP conversations during HF management. Positive attitudes towards ACP were associated with lower depressive symptoms [two-item Patient Health Questionnaire; odds ratio (OR): 0.75, 95% confidence interval (CI): 0.61-0.92, P-value: 0.006], marriage (OR: 2.53, 95% CI: 1.25-5.12, P-value: 0.010), and a high educational level (OR: 2.66, 95% CI: 1.28-5.56, P-value: 0.009), but not with severity of HF (represented by Seattle Heart Failure Model risk score). Regarding EOL care, while 'Saying what one wants to tell loved ones' (83.4%), 'Dying a natural death' (81.8%), and 'Being able to stay at one's favorite place' (75.6%) were the three most important factors for patients, preferences for 'Receiving sufficient treatment' (56.5%) and 'Knowing what to expect about future condition' (50.3%) were divergent. CONCLUSIONS: Despite patients' preferences for ACP conversations, there was a discrepancy between preference and engagement in ACP among patients hospitalized for HF. Patients' preferences regarding EOL care may differ; physicians need to consider the appropriate ACP approach to align with patients' care goals.

Imeglimin prevents heart failure with preserved ejection fraction by recovering the impaired unfolded protein response in mice subjected to cardiometabolic stress.

The pathogenesis of heart failure with preserved ejection fraction (HFpEF) in obese diabetic patients has been implicated in metainflammation. Increased expression of inducible nitric oxide synthase (iNOS) and dysfunction of the unfolded protein response (UPR), especially inositol-requiring enzyme 1α-X-box binding protein 1 (IRE1α-Xbp1s) signaling in the heart, have been associated with HFpEF. We investigated the effect of imeglimin, a potential new treatment for type 2 diabetes, on the pathogenesis of HFpEF. We induced obesity, impaired glucose tolerance, and cardiac hypertrophy with fibrosis, fat accumulation, and diastolic dysfunction in wild-type mice with a high-fat diet (HFD) and the nitric oxide synthase (NOS) inhibitor l-NAME for 16 weeks. Treatment with imeglimin starting at 10 weeks not only improved their abnormal systemic glucose metabolism and visceral obesity but also their cardiac abnormalities. We found that imeglimin suppressed the upregulation of iNOS, and restored the expression of Xbp1s and the expression of the E3 ubiquitin ligase STIP1 homology and U-box-containing protein 1 (STUB1), which is responsible for the degradation of Forkhead box protein O1 (FoxO1), a direct transcriptional target of Xbp1s. It also suppressed the excessive transcriptional activity of FoxO1, which is located downstream of Xbp1s and is involved in the form development of HFpEF and cardiac adipogenesis. Imeglimin also restored the expression of Glutathione peroxidase 4 (GPX4), which protects cells against excess lipid peroxidation and governs a novel form of programmed cell death, called ferroptosis.

MITOL/MARCH5 determines the susceptibility of cardiomyocytes to doxorubicin-induced ferroptosis by regulating GSH homeostasis.

MITOL/MARCH5 is an E3 ubiquitin ligase that plays a crucial role in the control of mitochondrial quality and function. However, the significance of MITOL in cardiomyocytes under physiological and pathological conditions remains unclear. First, to determine the significance of MITOL in unstressed hearts, we assessed the cellular changes with the reduction of MITOL expression by siRNA in neonatal rat primary ventricular cardiomyocytes (NRVMs). MITOL knockdown in NRVMs induced cell death via ferroptosis, a newly defined non-apoptotic programmed cell death, even under no stress conditions. This phenomenon was observed only in NRVMs, not in other cell types. MITOL knockdown markedly reduced mitochondria-localized GPX4, a key enzyme associated with ferroptosis, promoting accumulation of lipid peroxides in mitochondria. In contrast, the activation of GPX4 in MITOL knockdown cells suppressed lipid peroxidation and cell death. MITOL knockdown reduced the glutathione/oxidized glutathione (GSH/GSSG) ratio that regulated GPX4 expression. Indeed, the administration of GSH or N-acetylcysteine improved the expression of GPX4 and viability in MITOL-knockdown NRVMs. MITOL-knockdown increased the expression of the glutathione-degrading enzyme, ChaC glutathione-specific γ-glutamylcyclotransferase 1 (Chac1). The knockdown of Chac1 restored the GSH/GSSG ratio, GPX4 expression, and viability in MITOL-knockdown NRVMs. Further, in cultured cardiomyocytes stressed with DOX, both MITOL and GPX4 were reduced, whereas forced-expression of MITOL suppressed DOX-induced ferroptosis by maintaining GPX4 content. Additionally, MITOL knockdown worsened vulnerability to DOX, which was almost completely rescued by treatment with ferrostatin-1, a ferroptosis inhibitor. In vivo, cardiac-specific depletion of MITOL did not produce obvious abnormality, but enhanced susceptibility to DOX toxicity. Finally, administration of ferrostatin-1 suppressed exacerbation of DOX-induced myocardial damage in MITOL-knockout hearts. The present study demonstrates that MITOL determines the cell fate of cardiomyocytes via the ferroptosis process and plays a key role in regulating vulnerability to DOX treatment. (288/300).