Machine learning-based detection of sleep-disordered breathing in hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is often concomitant with sleep-disordered breathing (SDB), which can cause adverse cardiovascular events. Although an appropriate approach to SDB prevents cardiac remodelling, detection of concomitant SDB in patients with HCM remains suboptimal. Thus, we aimed to develop a machine learning-based discriminant model for SDB in HCM. METHODS: In the present multicentre study, we consecutively registered patients with HCM and performed nocturnal oximetry. The outcome was a high Oxygen Desaturation Index (ODI), defined as 3% ODI >10, which significantly correlated with the presence of moderate or severe SDB. We randomly divided the whole participants into a training set (80%) and a test set (20%). With data from the training set, we developed a random forest discriminant model for high ODI based on clinical parameters. We tested the ability of the discriminant model on the test set and compared it with a previous logistic regression model for distinguishing SDB in patients with HCM. RESULTS: Among 369 patients with HCM, 228 (61.8%) had high ODI. In the test set, the area under the receiver operating characteristic curve of the discriminant model was 0.86 (95% CI 0.77 to 0.94). The sensitivity was 0.91 (95% CI 0.79 to 0.98) and specificity was 0.68 (95% CI 0.48 to 0.84). When the test set was divided into low-probability and high-probability groups, the high-probability group had a higher prevalence of high ODI than the low-probability group (82.4% vs 17.4%, OR 20.9 (95% CI 5.3 to 105.8), Fisher's exact test p<0.001). The discriminant model significantly outperformed the previous logistic regression model (DeLong test p=0.03). CONCLUSIONS: Our study serves as the first to develop a machine learning-based discriminant model for the concomitance of SDB in patients with HCM. The discriminant model may facilitate cost-effective screening tests and treatments for SDB in the population with HCM.

Safety and feasibility of a novel total percutaneous post-closure technique after bedside Impella decannulation in patients with cardiogenic shock.

OBJECTIVES: The Impella (Abiomed) is a widely used percutaneous mechanical circulatory support device for high-risk percutaneous coronary intervention in patients with cardiogenic shock. This study aimed to determine the safety and feasibility of a non-angio-guided post-closure approach using the Perclose ProGlide (Abbott) to decannulate the Impella in the intensive care unit. METHODS: This retrospective study included consecutive patients who were successfully weaned from mechanical circulatory support using the Impella device between April 2019 and April 2022 at Hamamatsu University School of Medicine. Fifteen patients underwent complete post-closure of the femoral artery access sites at the bedside. Technical success of the post-closure hemostasis technique was defined as no evidence of bleeding or additional medical procedures after manual compression. The safety endpoints comprised the Valve Academic Research Consortium-3 and Bleeding Academic Research Consortium criteria. RESULTS: All patients achieved successful hemostasis with this novel technique without surgical conversion. There was no significant bleeding; however, procedure-related vessel occlusion was observed in 1 patient who was recanalized with balloon angioplasty. CONCLUSIONS: Bedside post-closure using the Perclose ProGlide device is a safe and feasible alternative to manual compression and surgical removal of the Impella device with low bleeding or vascular complications rates.

Recurrent Coronary Thrombus in a Patient with Chronic Immune Thrombocytopenia with Treatment Using Eltrombopag.

BACKGROUND: Eltrombopag, a nonpeptide thrombopoietin receptor agonist (TPO-RA), has been reported to be an effective therapy for chronic immune thrombocytopenia (ITP). However, a higher incidence of arterial and venous thromboembolic events was reported after using eltrombopag. CASE PRESENTATION: A 67-year-old man, treated with eltrombopag due to chronic ITP, was admitted due to acute coronary syndrome (ACS). Although coronary angiography revealed no occlusion, cardiac magnetic resonance imaging suggested a myocardial infarction in the territory of the left circumflex coronary artery. Three months after the ACS event, the obtuse marginal branches exhibited significant stenosis; hence, a percutaneous coronary intervention (PCI) was performed to implant a zotarolimus-eluting stent under the treatment of a dual antiplatelet therapy. However, stent thrombosis occurred 3 hours after PCI and required three other PCIs during the eltrombopag treatment. CONCLUSION: We present a case of an ITP patient, who experienced repeated coronary and stent thrombosis during the treatment with eltrombopag. We propose that the risk of ACS and consequent coronary stent thrombosis should be considered before the introduction of eltrombopag.

Glycogen synthase kinase-3ß opens mitochondrial permeability transition pore through mitochondrial hexokinase II dissociation.

Accumulating evidence has revealed pivotal roles of glycogen synthase kinase-3ß (GSK3ß) inactivation on cardiac protection. Because the precise mechanisms of cardiac protection against ischemia/reperfusion (I/R) injury by GSK3ß-inactivation remain elusive, we investigated the relationship between GSK3ß-mediated mitochondrial hexokinase II (mitoHK-II; a downstream target of GSK3ß) dissociation and mitochondrial permeability transition pore (mPTP) opening. In Langendorff-perfused hearts, GSK3ß inactivation by SB216763 improved the left ventricular-developed pressure and retained mitoHK-II binding after I/R. In permeabilized myocytes, GSK3ß depolarized mitochondrial membrane potential with accelerated mitochondrial calcein release (suggesting GSK3ß-mediated mPTP opening) and decreased mitoHK-II bindings. GSK3ß-mediated mPTP opening depended on mitoHK-II binding, i.e., it was accelerated by dissociation of mitoHK-II (dicyclohexylcarbodiimide) and attenuated by enhancement of mitoHK-II binding (dextran). However, inactivation of mitoHK-II by glucose-depletion or glucose-6-phosphate inhibited the GSK3ß-mediated mPTP opening. We conclude that GSK3ß-mediated mPTP opening may be involved in I/R injury and regulated by mitoHK-II binding and activity.

Eicosapentaenoic acid ameliorates palmitate-induced lipotoxicity via the AMP kinase/dynamin-related protein-1 signaling pathway in differentiated H9c2 myocytes.

BACKGROUND: Emerging evidence suggested the preferable effects of eicosapentaenoic acid (EPA; n-3 polyunsaturated fatty acid) against cardiac lipotoxicity, which worsens cardiac function by means of excessive serum free fatty acids due to chronic adrenergic stimulation under heart failure. Nonetheless, the precise molecular mechanisms remain elusive. In this study, we focused on dynamin-related protein-1 (Drp1) as a possible modulator of the EPA-mediated cardiac protection against cardiac lipotoxicity, and investigated the causal relation between AMP-activated protein kinase (AMPK) and Drp1. METHODS AND RESULTS: When differentiated H9c2 myocytes were exposed to palmitate (PAL; saturated fatty acid, 400µM) for 24h, these myocytes showed activation of caspases 3 and 7, enhanced caspase 3 cleavage, depolarized mitochondrial membrane potential, depleted intracellular ATP, and enhanced production of intracellular reactive oxygen species. These changes suggested lipotoxicity due to excessive PAL. PAL enhanced mitochondrial fragmentation with increased Drp1 expression, as well. EPA (50µM) restored the PAL-induced apoptosis, mitochondrial dysfunction, and mitochondrial fragmentation with increased Drp1 expression by PAL. EPA activated phosphorylation of AMPK, and pharmacological activation of AMPK by 5-aminoimidazole-4-carboxamide ribonucleotide ameliorated the PAL-induced apoptosis, mitochondrial dysfunction, and downregulated Drp1. An AMPK knockdown via RNA interference enhanced Drp1 expression and attenuated the protective effects of EPA against the PAL-induced lipotoxicity. CONCLUSION: EPA ameliorates the PAL-induced lipotoxicity via AMPK activation, which subsequently suppresses mitochondrial fragmentation and Drp1 expression. Our findings may provide new insights into the molecular mechanisms of EPA-mediated myocardial protection in heart failure.

Intracellular Renin Inhibits Mitochondrial Permeability Transition Pore via Activated Mitochondrial Extracellular Signal-Regulated Kinase (ERK) 1/2 during Ischemia in Diabetic Hearts.

Although beneficial effects of non-secreting intracellular renin (ns-renin) against ischemia have been reported, the precise mechanism remains unclear. In this study, we investigated the roles of ns-renin and mitochondrial extracellular signal-related kinase (ERK) 1/2 on mitochondrial permeability transition pore (mPTP) opening during ischemia in diabetes mellitus (DM) hearts. When isolated hearts from Wistar rats (non-DM hearts) and Goto-Kakizaki rats (DM hearts) were subjected to ischemia for 70 min by left anterior descending coronary artery ligation, DM hearts exhibited higher left ventricular (LV) developed pressure and lower LV end-diastolic pressure than non-DM hearts, suggesting ischemic resistance. In addition, DM hearts showed increased intracellular renin (int-renin, including secreting and non-secreting renin) in the ischemic area, and a direct renin inhibitor (DRI; aliskiren) attenuated ischemic resistance in DM hearts. ERK1/2 was significantly phosphorylated after ischemia in both whole cell and mitochondrial fractions in DM hearts. In isolated mitochondria from DM hearts, rat recombinant renin (r-renin) significantly phosphorylated mitochondrial ERK1/2, and hyperpolarized mitochondrial membrane potential (ΔΨm) in a U0126 (an inhibitor of mitogen-activated protein kinases/ERK kinases)-sensitive manner. R-renin also attenuated atractyloside (Atr, an mPTP opener)-induced ΔΨm depolarization and Atr-induced mitochondrial swelling in an U0126-sensitive manner in isolated mitochondria from DM hearts. Furthermore, U0126 attenuated ischemic resistance in DM hearts, whereas it did not alter the hemodynamics in non-DM hearts. Our results suggest that the increased int-renin during ischemia may inhibit mPTP opening through activation of mitochondrial ERK1/2, which may be involved in ischemic resistance in DM hearts.