Clinical Significance of the Triglyceride-Glucose Index in Patients Requiring Nonsurgical Intensive Care.

The evaluation of triglyceride-glucose (TyG) index has not been sufficient in patients requiring nonsurgical intensive care.A total of 3,906 patients who required intensive care were enrolled. We computed the TyG index using the value on admission by the following formula: ln [triglyceride (mg/dL) × glucose (mg/dL) /2]. Patients were divided into three groups according to the TyG index quartiles: low (quartile 1 [Q1]; TyG index ≤ 8.493, n = 977), middle (Q2/Q3; 8.494 ≤ TyG index ≤ 9.536, n = 1,953), and high (Q4; TyG index > 9.537, n = 976). The median (interquartile range) TyG index was 9.00 (8.50-9.54); acute coronary syndrome (ACS) had the highest TyG index among all etiologies at 9.12 (8.60-9.68). A multivariate logistic regression model showed that ACS (odds ratio [OR], 2.133; 95% confidence interval [CI], 1.783-2.552) were independently correlated with high TyG index. A Cox proportional hazards regression model revealed that, in ACS, the Q2/Q3 and Q4 groups were independent predictors of 30-day all-cause mortality (hazard ratio [HR], 1.778; 95% CI, 1.014-3.118; HR, 2.986; 95% CI, 1.680-5.308; respectively) and that in acute heart failure [AHF], the Q4 group was a converse independent predictor of 30-day all-cause mortality (HR, 0.488; 95% CI, 0.241-0.988).High TyG index was linked to ACS and negative outcomes in the ACS group; in contrast, low TyG index was associated with adverse outcomes in the AHF group.

Clinical Background and Coronary Artery Lesions Characteristics in Japanese Patients With Acute Coronary Syndrome Suffering Major Bleeding.

Background: Although the clinical factors that predict major bleeding in Western patients with acute coronary syndrome (ACS) are becoming elucidated, they have not been fully investigated, especially coronary lesion characteristics, in a Japanese population. Methods and Results: ACS patients (n=1,840) were divided into a "bleeding group" and a "no-bleeding group," according to whether they had major bleeding during the 2-year follow-up period, to investigate the prognostic effect of bleeding and the predictive factors of bleeding. Among them, patients who underwent primary percutaneous coronary intervention with optical coherence tomography (OCT) guidance (n=958) were examined to identify the effect of coronary lesion characteristics on bleeding. Of the 1,840 enrolled patients, 124 (6.7%) experienced major bleeding during the 2-year follow-up period. Incidence of cardiovascular death during the 2-year follow-up period was significantly higher among patients with major bleeding (26.4% vs. 8.5%, P=0.001). OCT examination showed that disrupted fibrous cap (DFC: 68% vs. 48%, P=0.014) and calcified plaque (63% vs. 42%, P=0.011) were more prevalent in the bleeding group. DFC was a predictor of major bleeding in the multivariate Cox proportional hazards analyses (hazard ratio 2.135 [95% confidence interval 1.070-4.263], P<0.001). Conclusions: ACS patients with major bleeding had poorer cardiac outcomes. Advanced atherosclerosis at the culprit lesion influences the higher incidence of major bleeding in ACS patients.

Comparisons of Patients Living Alone versus Living with Others in Acute Coronary Syndrome.

We aimed to examine the relationship of living arrangements (i.e., living alone or living with others) with background, clinical severity, preintervention culprit lesion plaque morphology, and clinical outcomes in patients with acute coronary syndrome (ACS). Among 1,683 consecutive patients with ACS, we retrospectively compared patients living alone ( n = 318) versus living with others ( n = 1,362). Optical coherence tomography (OCT) findings, which are high-resolution intracoronary imaging devices, were analyzed in patients with preintervention OCT and compared between patients living alone ( n = 174) versus those living with others ( n = 665). Older (median; 69 vs. 67 y, p = 0.046) and female (31 vs. 17%, p < 0.001) patients more frequently lived alone. Frequency of achieving a time interval of 6 hours or less from ACS onset to admission was lower in patients living alone (56 vs. 63%, p = 0.022). Clinical presentation was more severe in patients living alone (Killip II/III/IV; 27 vs. 22%, p = 0.029). Plaque morphology evaluated by OCT was similar between groups (plaque rapture; 48 vs. 48%, p = 0.171). Kaplan-Meier analyses revealed higher rates of cardiac mortality during 2-year follow-up period in patients living alone [13.9 vs. 8.5%, hazard ratio (HR) 1.604, 95% confidence interval (CI) 1.112-2.313, p = 0.010]. After traditional cardiovascular risk factors and clinical severity upon admission had been adjusted, living alone was an independent predictor of cardiac mortality in ACS patients (HR 1.582, 95% CI 1.056-2.371, p = 0.026). Living alone was independently associated with 2-year cardiacmortality in ACS patients after adjusting for background and presentation and might be unrelated to the development of atherosclerosis.

Timing and Degree of Acute Kidney Injury in Patients Requiring Non-Surgical Intensive Care.

BACKGROUND: The degree and timing of acute kidney injury (AKI) on admission and during hospitalization in patients requiring non-surgical intensive care remain unclear.Methods and Results: In this study, 3,758 patients requiring intensive care were analyzed retrospectively. AKI was defined based on the ratio of serum creatinine concentrations recorded at each time point (i.e., on admission and during the first 5 days in the intensive care unit and during hospitalization) to those measured at baseline. Patients were grouped by combining AKI severity (RIFLE class) and timing (i.e., from admission to 5 days [A-5D]; from 5 days to hospital discharge [5D-HD]) as follows: No-AKI; New-AKI (no AKI to Class R [risk; ≥1.5-fold increase in serum creatinine], I [injury; ≥2.0-fold increase in serum creatinine], and F [failure; ≥3.0-fold increase in serum creatinine or receiving dialysis during hospitalization]); Stable-AKI (Class R to R; Class I to I); and Worsening-AKI (Class R to I or F; Class I to F). Multivariate logistic regression analysis indicated that 730-day mortality was independently associated with Class R, I, and F on admission; Class I and F during the 5D-H period; and New-AKI and Worsening-AKI during A-5D and 5D-HD. CONCLUSIONS: AKI on admission, even Class R, was associated with a poor prognosis. An increase in RIFLE class during hospitalization was identified as an important factor for poor prognosis in patients requiring intensive care.

Organ dysfunction, injury, and failure in cardiogenic shock.

BACKGROUND: Cardiogenic shock (CS) is caused by primary cardiac dysfunction and induced by various and heterogeneous diseases (e.g., acute impairment of cardiac performance, or acute or chronic impairment of cardiac performance). MAIN BODY: Although a low cardiac index is a common finding in patients with CS, the ventricular preload, pulmonary capillary wedge pressure, central venous pressure, and systemic vascular resistance might vary between patients. Organ dysfunction has traditionally been attributed to the hypoperfusion of the organ due to either progressive impairment of the cardiac output or intravascular volume depletion secondary to CS. However, research attention has recently shifted from this cardiac output ("forward failure") to venous congestion ("backward failure") as the most important hemodynamic determinant. Both hypoperfusion and/or venous congestion by CS could lead to injury, impairment, and failure of target organs (i.e., heart, lungs, kidney, liver, intestines, brain); these effects are associated with an increased mortality rate. Treatment strategies for the prevention, reduction, and reversal of organ injury are warranted to improve morbidity in these patients. The present review summarizes recent data regarding organ dysfunction, injury, and failure. CONCLUSIONS: Early identification and treatment of organ dysfunction, along with hemodynamic stabilization, are key components of the management of patients with CS.

Time-Dependent Changes in N-Terminal Pro-Brain Natriuretic Peptide and B-Type Natriuretic Peptide Ratio During Hospitalization for Acute Heart Failure.

The time-dependent changes in the simultaneous evaluation of B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) levels during hospitalization for acute heart failure (AHF) remain obscure.A total of 356 AHF patients were analyzed. Blood samples were collected within 15 minutes of admission (Day 1), 48-120 hours (Day 2-5) and between days 7 and 21 (Before-discharge). Plasma BNP and serum NT-proBNP were significantly decreased on Days 2-5 and Before-discharge in comparison to Day 1, but the NT-proBNP/BNP ratio was not changed. Patients were divided into 2 groups according to the median NT-proBNP/BNP (N/B) ratio on Day 2-5 (Low-N/B versus High-N/B). A multivariate logistic regression model showed that age (per 1-year increase), serum creatinine (per 1.0-mg/dL increase), and serum albumin (per 1.0-mg/dL decrease) were independently associated with High-N/B (odds ratio [OR]: 1.071, 95%confidence interval [CI]: 1.036-1.108, OR: 1.190, 95%CI: 1.121-1.264 and OR: 2.410, 95%CI: 1.121-5.155, respectively). Kaplan-Meier curve analysis showed that the High-N/B group had a significantly poorer prognosis than the Low-N/B group, and a multivariate Cox regression model revealed that High-N/B was an independent predictor of 365-day mortality (hazard ratio [HR]: 1.796, 95%CI: 1.041-3.100) and HF events (HR: 1.509, 95%CI: 1.007-2.263). The same trend in prognostic impact was significantly observed in both low and high delta-BNP cohorts (< 55% and ≥ 55% BNP value on the start date/BNP value at 2-5-days).A high NT-proBNP/BNP ratio on Day 2-5 was associated with non-cardiac conditions and was associated with adverse outcomes even if BNP was adequately decreased by the treatment of AHF.

Evaluation of Plasma Xanthine Oxidoreductase (XOR) Activity in Patients with Cardiopulmonary Arrest.

Plasma xanthine oxidoreductase (XOR) activity in patients with cardiopulmonary arrest (CPA) has not yet been studied.A total of 1,158 patients who required intensive care and 231 control patients who attended a cardiovascular outpatient clinic were prospectively analyzed. Blood samples were collected within 15 minutes of admission from patients in intensive care patients, which were divided into a CPA group (n = 1,053) and a no-CPA group (n = 105). Plasma XOR activity was compared between the 3 groups and factors independently associated with extremely elevated XOR activity were identified using a multivariate logistic regression model. Plasma XOR activity in the CPA group (median, 1,030.0 pmol/hour/mL; range, 233.0-4,240.0 pmol/hour/mL) was significantly higher than in the no-CPA group (median, 60.2 pmol/hour/mL; range, 22.5-205.0 pmol/hour/mL) and control group (median, 45.2 pmol/hour/mL; range, 19.3-98.8 pmol/hour/mL). The regression model showed that out-of-hospital cardiac arrest (OHCA) (yes, odds ratio [OR]: 2.548; 95% confidence interval [CI]: 1.098-5.914; P = 0.029) and lactate levels (per 1.0 mmol/L increase, OR: 1.127; 95% CI: 1.031-1.232; P = 0.009) were independently associated with high plasma XOR activity (≥ 1,000 pmol/hour/mL). Kaplan-Meier curve analysis indicated that the prognosis, including all-cause death within 30 days, was significantly poorer in high-XOR patients (XOR ≥ 6,670 pmol/hour/mL) than in the other patients.Plasma XOR activity was extremely high in patients with CPA, especially in OHCA. This would be associated with a high lactate value and expected to eventually lead to adverse outcome in patients with CPA.

Effect of sacubitril/valsartan on natriuretic peptide in patients with compensated heart failure.

The time-dependent changes in the natriuretic peptide families during sacubitril/valsartan (S/V) treatment remain obscure in the Asian heart failure (HF) cohort. Eighty-one outpatients with compensated HF were analyzed. The patients were divided into two groups based on the administration of S/V (n = 42) or angiotensin converting enzyme inhibitor (ACE-I; n = 39). Changes to the natriuretic peptide families and the daily dose of loop diuretics were evaluated 3 and 6 months after the intervention. The atrial natriuretic peptide (ANP) level was significantly increased (102 [63-160] pg/mL to 283 [171-614] pg/mL [3 months]; 409 [210-726] pg/mL [6 months]) in the S/V group but not in the ACE-I group. The dose of furosemide was significantly decreased during the six-month follow-up period in the S/V group (40 [20-40] mg to 20 [10-20] mg) but not in the ACE-I group. A multivariate logistic regression model showed that the presence of persistent atrial fibrillation (AF) and HF with a preserved left ventricular ejection fraction (HFpEF) was independently associated with a high delta-ANP ratio (≥ 4.5 ANP value on the start date/ANP value at 6 months; the mean value was used as the cutoff value) (odds ratio [OR]: 4.649, 95% CI 1.032-20.952 and OR: 7.558, 95% CI 1.427-40.042). The plasma level of ANP was increased, and the loop diuretic dose was decreased by the addition of neprilysin inhibitor therapy in patients with compensated HF. In patients with HFpEF and complicated persistent AF, neprilysin inhibitor therapy was associated with an increase in ANP.

Trends in Sudden Death Following Admission for Acute Heart Failure.

Few studies on sudden death (SD) after admission for acute heart failure (AHF) have been published. A total of 1,664 patients with AHF were enrolled in this study, and 1,261 patients who were successfully followed up during the first year after admission were analyzed. The primary end point was SD, which was defined as out-of-hospital cardiac arrest. The median follow-up period from admission was 1,008 days (range 408 to 2,132). In total, 505 patients (40.0%) died: 341 (67.5%) died of cardiovascular causes and 55 (10.9%) died of other causes. Of the 505 who died, 80 (15.8%) experienced SD. The proportion of SDs increased in the later phases of follow-up (0 to 1 year, 10.3%; 1 to 2 years, 18.0%; 2 to 5 years, 18.8%; ≥5 years, 28.2%; p <0.001). A multivariate logistic regression model showed that younger age was independently associated with SD (60 to 69 years: odds ratio 2.249, 95% confidence interval 1.060 to 4.722; <60 years: odds ratio 3.863, 95% confidence interval 1.676 to 8.905). Kaplan-Meier curves showed that the incidence of cardiovascular death was highest during the acute phase, whereas the incidence of SD increased gradually over the entire follow-up period. In conclusion, the incidence of SD was surprisingly high in patients with AHF, accounting for 16% of long-term mortality. The proportion of SDs increased during the very late follow-up phases.

Type III procollagen peptide level can indicate liver dysfunction associated with volume overload in acute heart failure.

AIM: The role of serum type III procollagen peptide (P3P) level in the acute phase of acute heart failure (AHF) requires clarification. We hypothesized that serum P3P level is temporarily higher during the acute phase, reflecting liver dysfunction due to congestion. METHODS AND RESULTS: A total of 800 AHF patients were screened, and data from 643 patients were analysed. Heart failure was diagnosed by the treating physician according to the European Society of Cardiology (ESC) guidelines, and included patients being treated with high-concentration oxygen inhalation (including mechanical support) for orthopnea, inotrope administration, or mechanical support for low blood pressure, and various types of diuretics for peripheral or pulmonary oedema. In all cases, diuretics or vasodilators were administered to treat AHF. The patients were divided into three groups according to their quartile (Q) serum P3P level: low-P3P (Q1, P3P ≤ 0.6 U/mL), mid-P3P (Q2/Q3, 0.6 < P3P <1.2 U/mL), and high-P3P (Q4, P3P ≥ 1.2 U/mL). The plasma volume status (PVS) was calculated using the following formula: ([actual PV - ideal PV]/ideal PV) × 100 (%). The primary endpoint was 365 day mortality. A Kaplan-Meier curve analysis showed that prognoses, including all-cause mortality and heart failure events within 365 days, were significantly (P < 0.001) worse in the high-P3P group when compared with the mid-P3P and low-P3P groups. A multivariate logistic regression analysis showed that high PVS (Q4, odds ratio [OR]: 4.702, 95% CI: 2.012-20.989, P < 0.001), high fibrosis-4 index (Q4, OR: 2.627, 95% CI: 1.311-5.261, P = 0.006), and low estimated glomerular filtration rate per 10 mL/min/1.73 m2 decrease (OR: 1.996, 95% CI: 1.718-2.326, P < 0.001) were associated with high P3P values. The Kaplan-Meier curve analysis demonstrated a significantly lower survival rate, as well as a higher rate of heart failure events, in the high-P3P and high-PVS groups when compared with the other groups. A multivariate Cox regression model identified high P3P level and high PVS as an independent predictor of 365 day all-cause mortality (hazard ratio [HR]: 2.249; 95% CI: 1.081-3.356; P = 0.026) and heart failure events (HR: 1.586, 95% CI: 1.005-2.503, P = 0.048). CONCLUSION: A high P3P level during the acute phase of AHF served as a comprehensive biomarker of liver dysfunction with volume overload (i.e. liver congestion) and renal dysfunction. A high P3P level at admission may be able to predict adverse outcomes in AHF patients.

Helicopter emergency medical service for patients with acute coronary syndrome: selection validity and impact on clinical outcomes.

Helicopter emergency medical service (HEMS) has the potential to improve prognosis for acute coronary syndrome (ACS). However, adequacy and effectiveness of HEMS have not been fully evaluated. A total of 862 ACS patients transferred by emergency medical services were divided into two groups: patients transferred by HEMS (n = 171) or by ground ambulance (GA; n = 691). Among them, angiography images for 718 patients (149 in HEMS and 569 in GA group) and optical coherence tomography (OCT) images for 374 patients (75 in HEMS and 299 in GA groups) were analyzed. Additional analysis to compare 2-year cardiac mortality between groups was conducted following propensity score matching to adjust for inter-group differences. ST-segment elevation myocardial infarction (81% vs. 66%, p < 0.001) and cardiogenic shock (Killip IV; 20% vs. 10%, p < 0.001) at admission were more prevalent in HEMS than GA group. Time from admission to balloon angioplasty was shorter in HEMS group (median 54 min vs. 69 min, p < 0.001). Antegrade coronary flow was worse in HEMS group (TIMI flow grade 0 or 1; 68% vs. 51%, p < 0.001). Plaque rupture was more frequently detected by OCT in HEMS group (68% vs. 49%, p = 0.029). Following propensity score matching, the incidence of cardiac death was significantly lower in HEMS group (6.3% vs. 14.9%, p = 0.019). In conclusion, severe ACS patients requiring early reperfusion were appropriately triaged and transferred more rapidly by HEMS. Lower mortality in HEMS group after propensity score matching suggests that HEMS may improve cardiac mortality in ACS patients.

Ulk1-dependent alternative mitophagy plays a protective role during pressure overload in the heart.

AIMS: Well-controlled mitochondrial homeostasis, including a mitochondria-specific form of autophagy (hereafter referred to as mitophagy), is essential for maintaining cardiac function. The molecular mechanism mediating mitophagy during pressure overload (PO) is poorly understood. We have shown previously that mitophagy in the heart is mediated primarily by Atg5/Atg7-independent mechanisms, including Unc-51-like kinase 1 (Ulk1)-dependent alternative mitophagy, during myocardial ischaemia. Here, we investigated the role of alternative mitophagy in the heart during PO-induced hypertrophy. METHODS AND RESULTS: Mitophagy was observed in the heart in response to transverse aortic constriction (TAC), peaking at 3-5 days. Whereas mitophagy is transiently up-regulated by TAC through an Atg7-dependent mechanism in the heart, peaking at 1 day, it is also activated more strongly and with a delayed time course through an Ulk1-dependent mechanism. TAC induced more severe cardiac dysfunction, hypertrophy, and fibrosis in ulk1 cardiac-specific knock-out (cKO) mice than in wild-type mice. Delayed activation of mitophagy was characterized by the co-localization of Rab9 dots and mitochondria and phosphorylation of Rab9 at Ser179, major features of alternative mitophagy. Furthermore, TAC-induced decreases in the mitochondrial aspect ratio were abolished and the irregularity of mitochondrial cristae was exacerbated, suggesting that mitochondrial quality control mechanisms are impaired in ulk1 cKO mice in response to TAC. TAT-Beclin 1 activates mitophagy even in Ulk1-deficient conditions. TAT-Beclin 1 treatment rescued mitochondrial dysfunction and cardiac dysfunction in ulk1 cKO mice during PO. CONCLUSION: Ulk1-mediated alternative mitophagy is a major mechanism mediating mitophagy in response to PO and plays an important role in mediating mitochondrial quality control mechanisms and protecting the heart against cardiac dysfunction.

Successful treatment of a patient with type-A acute aortic dissection with emergent percutaneous coronary intervention and thoracic endovascular aortic repair under percutaneous cardiopulmonary support: a case report.

Background: Type-A acute aortic dissection (AAD) with acute coronary involvement can be instantly fatal. The patient's haemodynamics can easily collapse, so rapid decisions regarding treatment strategy are essential. Case summary: A 76-year-old man requested an ambulance because of sudden back pain and paraplegia. He was admitted to the emergency room with cardiogenic shock due to acute myocardial infarction with ST-segment elevation. Computed tomography angiography revealed a thrombosed AAD from the ascending to the distal aorta after the renal artery bifurcation, suggesting a retrograde DeBakey type IIIb (DeBakey IIIb + r, Stanford type-A) dissection. He suddenly developed ventricular fibrillation with cardiac arrest and haemodynamic collapse. We thus performed percutaneous coronary intervention (PCI) and thoracic endovascular aortic repair under percutaneous cardiopulmonary support (PCPS). Percutaneous cardiopulmonary support and respiratory support were withdrawn 5 and 12 days after admission, respectively. The patient was transferred to the general ward on Day 28; he was eventually discharged to a rehabilitation hospital on Day 60, having recovered completely. Conclusion: Immediate decisions regarding treatment strategy are essential. Non-invasive emergent treatment strategies (such as PCI and TEVAR under PCPS) may be options for critically ill patients with type-A AAD.

Successful Treatment of Thrombocytopenia, Anasarca, Fever, Reticulin Myelofibrosis/Renal Insufficiency, and Organomegaly Syndrome Using Plasma Exchange Followed by Rituximab in the Intensive Care Unit.

Thrombocytopenia, anasarca, fever, reticulin myelofibrosis/renal insufficiency, and organomegaly (TAFRO) syndrome is treated using corticosteroids and/or immunosuppressive agents as first-line therapy. We report the case of a 69-year-old female with TAFRO syndrome in which the patient presented multiple organ failure and steroid resistance, which was successfully treated using plasma exchange (PE) followed by rituximab. Decisions regarding the next treatment, including PE, are urgent for patients with steroid-resistant TAFRO syndrome. Since it is considered that immunosuppressive agents may be removed by PE, the performance of PE before treatment with immunosuppressive agents might be an option for steroid-resistant TAFRO syndrome.

The Prognostic Impact of Hospital Transfer after Admission due to Acute Heart Failure.

The prognostic impact of transfer to another hospital among acute heart failure (AHF) patients has not been well elucidated.Of the 800 AHF patients analyzed, 682 patients were enrolled in this study for analysis. The subjects were divided into two groups according to their discharge location: discharge home (Group-H, n = 589) or transfer to another hospital for rehabilitation (Group-T, n = 93). The Kaplan-Meier curves revealed a poorer prognosis, including all-cause death and heart failure (HF) events (death, readmission-HF), in Group-T than that in Group-H (P < 0.001, respectively). A multivariate Cox regression model showed that Group-T was an independent predictor of 365-day all-cause death (hazard ratio: 2.618, 95% confidence interval [CI]: 1.510-4.538, P = 0.001). The multivariate logistic regression analysis showed that aging (per 1-year-old increase, odds ratio [OR]: 1.056, 95% CI: 1.028-1.085, P < 0.001), female gender (OR: 2.128, 95% CI: 1.287-3.521, P = 0.003), endotracheal intubation during hospitalization (OR: 2.074, 95% CI: 1.093-3.936, P = 0.026), and increased Controlling Nutritional Status score on admission (per 1.0-point increase, OR: 1.247, 95% CI: 1.131-1.475, P < 0.001) were associated with transfer to another hospital after AHF admission. The prognosis, including all-cause death, was determined to be significantly poorer in patients who were transferred to another hospital, as their activities of daily living were noted to lessen before discharge (n = 11) compared to others (n = 82).Elderly AHF patients suffering from malnutrition were difficult to discharge home after AHF admission, and transfer to another hospital only led to adverse outcomes. Appropriate rehabilitation during definitive hospitalization appears necessary for managing elderly patients in the HF pandemic era.

Ser9 phosphorylation of GSK-3ß promotes aging in the heart through suppression of autophagy.

INTRODUCTION: Glycogen synthase kinase-3ß (GSK-3ß) is a serine/threonine kinase and a negative regulator of cardiac hypertrophy. Phosphorylation of GSK-3ß at Ser9 negatively regulates its kinase activity. The role of GSK-3ß in cardiac aging remains poorly understood. AIM: The study aimed to elucidate the role of GSK-3ß Ser9 phosphorylation in mediating cardiac aging and the underlying mechanism. METHODS AND RESULTS: Phosphorylation of GSK-3ß at Ser9 and the levels of ß-catenin and Mcl-1 were increased in the mouse heart during aging, suggesting that GSK-3ß is inactivated during aging in the heart. Age-induced cardiac hypertrophy, fibrosis, left ventricular dysfunction, and increases in cardiomyocyte apoptosis and senescence were all attenuated in constitutively active GSK-3ßS9A knock-in (KI) mice compared to littermate wild type mice. Although autophagy is inhibited in the heart during aging, KI of GSK-3ßS9A reversed the age-associated decline in autophagy in the mouse heart. GSK-3ß directly phosphorylates Ulk1, a regulator of autophagy, at Ser913, thereby stimulating autophagy in cardiomyocytes. Ulk1Ser913A KI mice exhibited decreased autophagic flux and increased senescence in cardiomyocytes. CONCLUSION: Our results suggest that GSK-3ß is inactivated during aging through Ser9 phosphorylation, which in turn plays an important role in mediating cardiac aging. GSK-3ß promotes autophagy through phosphorylation of Ulk1 at Ser913, which in turn prevents aging in the heart.

Alternative Mitophagy Protects the Heart Against Obesity-Associated Cardiomyopathy.

RATIONALE: Obesity-associated cardiomyopathy characterized by hypertrophy and mitochondrial dysfunction. Mitochondrial quality control mechanisms, including mitophagy, are essential for the maintenance of cardiac function in obesity-associated cardiomyopathy. However, autophagic flux peaks at around 6 weeks of high-fat diet (HFD) consumption and declines thereafter. OBJECTIVE: We investigated whether mitophagy is activated during the chronic phase of cardiomyopathy associated with obesity (obesity cardiomyopathy) after general autophagy is downregulated and, if so, what the underlying mechanism and the functional significance are. METHODS AND RESULTS: Mice were fed either a normal diet or a HFD (60 kcal% fat). Mitophagy, evaluated using Mito-Keima, was increased after 3 weeks of HFD consumption and continued to increase after conventional mechanisms of autophagy were inactivated, at least until 24 weeks. HFD consumption time-dependently upregulated both Ser555-phosphorylated Ulk1 (unc-51 like kinase 1) and Rab9 (Ras-related protein Rab-9) in the mitochondrial fraction. Mitochondria were sequestrated by Rab9-positive ring-like structures in cardiomyocytes isolated from mice after 20 weeks of HFD consumption, consistent with the activation of alternative mitophagy. Increases in mitophagy induced by HFD consumption for 20 weeks were abolished in cardiac-specific ulk1 knockout mouse hearts, in which both diastolic and systolic dysfunction were exacerbated. Rab9 S179A knock-in mice, in which alternative mitophagy is selectively suppressed, exhibited impaired mitophagy and more severe cardiac dysfunction than control mice following HFD consumption for 20 weeks. Overexpression of Rab9 in the heart increased mitophagy and protected against cardiac dysfunction during HFD consumption. HFD-induced activation of Rab9-dependent mitophagy was accompanied by upregulation of TFE3 (transcription factor binding to IGHM enhancer 3), which plays an essential role in transcriptional activation of mitophagy. CONCLUSIONS: Ulk1-Rab9-dependent alternative mitophagy is activated during the chronic phase of HFD consumption and serves as an essential mitochondrial quality control mechanism, thereby protecting the heart against obesity cardiomyopathy.

Clinical Significance of Low-Triiodothyronine Syndrome in Patients Requiring Non-Surgical Intensive Care　- Triiodothyronine Is a Comprehensive Prognostic Marker for Critical Patients With Cardiovascular Disease.

Background: Low-triiodothyronine (T3) syndrome is a known complication in intensive care unit (ICU) patients, but the underlying mechanisms and prognostic impact are unclear. Methods and Results: This study retrospectively enrolled 2,976 patients who required care in the ICU. Of these patients, 2,425 were euthyroid and were divided into normal (n=1,666; free T3 [FT3] ≥1.88 µIU/L) and low-FT3 (n=759; FT3 <1.88 µIU/L) groups. Multivariate logistic regression analysis revealed that prognostic nutritional index >46.03 (odds ratio [OR] 2.392; 95% confidence interval [CI] 1.904-3.005), age (per 1-year increase; OR 1.022; 95% CI 1.013-1.031), creatinine (per 0.1-mg/dL increase; OR 1.019; 95% CI 1.014-1.024), and C-reactive protein (per 1-mg/dL increase; OR 1.123; 95% CI 1.095-1.151) were independently associated with low FT3. Survival rates (within 365 days) were significantly lower in the low-FT3 group. A multivariate Cox regression model showed that low FT3 was an independent predictor of 365-day mortality (hazard ratio 1.785; 95% CI 1.387-2.297). Low-T3 syndrome was significantly more frequent in patients with non-cardiovascular than cardiovascular diseases (73.5% vs. 25.8%). Prognosis was significantly poorer in the low-FT3 than normal group for patients with cardiovascular disease, particularly those with acute coronary syndrome and acute heart failure. Conclusions: Low-T3 syndrome was associated with aging, inflammatory reaction, malnutrition, and renal insufficiency and could lead to adverse outcomes in patients admitted to a non-surgical ICU.

Impact of Low Body Mass Index on Features of Coronary Culprit Plaques and Outcomes in Patients With Acute Coronary Syndrome.

The mechanisms behind poorer cardiac outcomes in underweight patients with acute coronary syndrome (ACS) are not understood and features of coronary culprit lesions in underweight ACS patients have not been fully examined. A total of 1,683 patients with ACS were divided into 4 groups according to body mass index (BMI): <18.5 (n = 73), 18.5 to 24.9 (n = 995), 25 to 29.9 (n = 488), and ≥30 (n = 117). Angiography and optical coherence tomography (OCT) images were analyzed for 1,428 of these patients who had primary percutaneous coronary intervention (PCI) and 838 who had primary PCI with OCT guidance, respectively. Diabetes (p <0.001), hypertension (p <0.001), and dyslipidemia (p <0.001) were less prevalent in BMI <18.5. Statin prescription at discharge was less frequent in the BMI <18.5 group (p <0.001). Quantitative coronary angiography analyses revealed smaller reference vessel (p = 0.001) and minimum lumen diameters after PCI (p = 0.019) and OCT revealed longer lipidic plaque length (p = 0.029) in the BMI <18.5 group. Kaplan-Meier analyses revealed higher rates of cardiac mortality (p <0.001) and major bleeding (p = 0.034) during the 2-year follow-up in the BMI <18.5 group. After adjusting for traditional cardiovascular risk factors, BMI <18.5 independently predicted 2-year cardiac mortality (hazard ratio 1.917 [95% confidence interval [1.082 to 3.397], p = 0.026). In conclusion, being underweight contributed to poorer cardiac outcomes in established ACS population. Smaller minimum lumen diameter after PCI and further progressed atherosclerosis at the culprit lesions despite their lower prevalence of comorbid metabolic risk factors may be related partly to poorer cardiac outcomes.