Vaccine Therapy for Heart Failure Targeting the Inflammatory Cytokine Igfbp7.

BACKGROUND: The heart comprises many types of cells such as cardiomyocytes, endothelial cells (ECs), fibroblasts, smooth muscle cells, pericytes, and blood cells. Every cell type responds to various stressors (eg, hemodynamic overload and ischemia) and changes its properties and interrelationships among cells. To date, heart failure research has focused mainly on cardiomyocytes; however, other types of cells and their cell-to-cell interactions might also be important in the pathogenesis of heart failure. METHODS: Pressure overload was imposed on mice by transverse aortic constriction and the vascular structure of the heart was examined using a tissue transparency technique. Functional and molecular analyses including single-cell RNA sequencing were performed on the hearts of wild-type mice and EC-specific gene knockout mice. Metabolites in heart tissue were measured by capillary electrophoresis-time of flight-mass spectrometry system. The vaccine was prepared by conjugating the synthesized epitope peptides with keyhole limpet hemocyanin and administered to mice with aluminum hydroxide as an adjuvant. Tissue samples from heart failure patients were used for single-nucleus RNA sequencing to examine gene expression in ECs and perform pathway analysis in cardiomyocytes. RESULTS: Pressure overload induced the development of intricately entwined blood vessels in murine hearts, leading to the accumulation of replication stress and DNA damage in cardiac ECs. Inhibition of cell proliferation by a cyclin-dependent kinase inhibitor reduced DNA damage in ECs and ameliorated transverse aortic constriction-induced cardiac dysfunction. Single-cell RNA sequencing analysis revealed upregulation of Igfbp7 (insulin-like growth factor-binding protein 7) expression in the senescent ECs and downregulation of insulin signaling and oxidative phosphorylation in cardiomyocytes of murine and human failing hearts. Overexpression of Igfbp7 in the murine heart using AAV9 (adeno-associated virus serotype 9) exacerbated cardiac dysfunction, while EC-specific deletion of Igfbp7 and the vaccine targeting Igfbp7 ameliorated cardiac dysfunction with increased oxidative phosphorylation in cardiomyocytes under pressure overload. CONCLUSIONS: Igfbp7 produced by senescent ECs causes cardiac dysfunction and vaccine therapy targeting Igfbp7 may be useful to prevent the development of heart failure.

Development of a rapamycin-inducible protein-knockdown system in the unicellular red alga Cyanidioschyzon merolae.

An inducible protein-knockdown system is highly effective for investigating the functions of proteins and mechanisms essential for the survival and growth of organisms. However, this technique is not available in photosynthetic eukaryotes. The unicellular red alga Cyanidioschyzon merolae possesses a very simple cellular and genomic architecture and is genetically tractable but lacks RNA interference machinery. In this study, we developed a protein-knockdown system in this alga. The constitutive system utilizes the destabilizing activity of the FRB domain of human target of rapamycin (TOR) kinase or its derivatives to knock down target proteins. In the inducible system, rapamycin treatment induces the heterodimerization of the human FKBP12-rapamycin binding (FRB) domain fused to the target proteins with the human FK506-binding protein 12 (FKBP) fused to S-phase kinase associated protein 1 (SKP1) or Cullin 1 (CUL1), subunits of the SCF E3 ubiquitin ligase. This results in the rapid degradation of the target proteins through the ubiquitin-proteasome pathway. With this system, we successfully degraded endogenous essential proteins such as the chloroplast division protein Dynamin related protein 5B (DRP5B) and E2 transcription factor (E2F), a regulator of the G1/S transition, within 2-3 hours after rapamycin administration, enabling the assessment of resulting phenotypes. This rapamycin-inducible protein-knockdown system contributes to the functional analysis of genes whose disruption leads to lethality.

Life cycle and functional genomics of the unicellular red alga Galdieria for elucidating algal and plant evolution and industrial use.

Sexual reproduction is widespread in eukaryotes; however, only asexual reproduction has been observed in unicellular red algae, including Galdieria, which branched early in Archaeplastida. Galdieria possesses a small genome; it is polyextremophile, grows either photoautotrophically, mixotrophically, or heterotrophically, and is being developed as an industrial source of vitamins and pigments because of its high biomass productivity. Here, we show that Galdieria exhibits a sexual life cycle, alternating between cell-walled diploid and cell wall-less haploid, and that both phases can proliferate asexually. The haploid can move over surfaces and undergo self-diploidization or generate heterozygous diploids through mating. Further, we prepared the whole genome and a comparative transcriptome dataset between the diploid and haploid and developed genetic tools for the stable gene expression, gene disruption, and selectable marker recycling system using the cell wall-less haploid. The BELL/KNOX and MADS-box transcription factors, which function in haploid-to-diploid transition and development in plants, are specifically expressed in the haploid and diploid, respectively, and are involved in the haploid-to-diploid transition in Galdieria, providing information on the missing link of the sexual life cycle evolution in Archaeplastida. Four actin genes are differently involved in motility of the haploid and cytokinesis in the diploid, both of which are myosin independent and likely reflect ancestral roles of actin. We have also generated photosynthesis-deficient mutants, such as blue-colored cells, which were depleted in chlorophyll and carotenoids, for industrial pigment production. These features of Galdieria facilitate the understanding of the evolution of algae and plants and the industrial use of microalgae.

CZON-cutter - a CRISPR-Cas9 system for multiplexed organelle imaging in a simple unicellular alga.

The unicellular alga Cyanidioschyzon merolae has a simple cellular structure; each cell has one nucleus, one mitochondrion, one chloroplast and one peroxisome. This simplicity offers unique advantages for investigating organellar proliferation and the cell cycle. Here, we describe CZON-cutter, an engineered clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR-associated nuclease 9 (Cas9) system for simultaneous genome editing and organellar visualization. We engineered a C. merolae strain expressing a nuclear-localized Cas9-Venus nuclease for targeted editing of any locus defined by a single-guide RNA (sgRNA). We then successfully edited the algal genome and visualized the mitochondrion and peroxisome in transformants using fluorescent protein reporters with different excitation wavelengths. Fluorescent protein labeling of organelles in living transformants allows us to validate phenotypes associated with organellar proliferation and the cell cycle, even when the edited gene is essential. Combined with the exceptional biological features of C. merolae, CZON-cutter will be instrumental for investigating cellular and organellar division in a high-throughput manner. This article has an associated First Person interview with the first author of the paper.

Cost-Effectiveness of Management for Hospitalized Patients.

The cost and/or cost-effectiveness for inpatient management according to the gender of attending physicians remain to be elucidated.Hospitalization costs were extracted from the Diagnosis Procedure Combination (DPC) -based payment system. Using a dataset of 7,457 hospitalized patients with cardiovascular diseases in our hospital from 2012 to 2018, we compared the actual cost of inpatient management by female cardiologists with that by male cardiologists. Next, we estimated the cost-effectiveness of inpatient management according to the gender of the attending cardiologist. The cost of initial hospitalization per patient was similar between the patients treated by a female or male middle-grade cardiologist ($17,527 ± 14,158, versus $17,358 ± 15,183, P = 0.69). As an analysis on cost-effectiveness, the incremental cost of hospitalization managed by male middle-grade cardiologists was $67 per patient as compared with female middle-grade cardiologists. Concordantly, evaluation of the incremental cost-effectiveness ratio per quality-adjusted life year gained showed that the inpatient management by female cardiologists was dominant over that by male cardiologists.Inpatient management by female cardiologists was more cost-effective as compared with that by male cardiologists. Physician gender might have a considerable effect on medical economics.

A cotransformation system of the unicellular red alga Cyanidioschyzon merolae with blasticidin S deaminase and chloramphenicol acetyltransferase selectable markers.

BACKGROUND: The unicellular red alga Cyanidioschyzon merolae exhibits a very simple cellular and genomic architecture. In addition, procedures for genetic modifications, such as gene targeting by homologous recombination and inducible/repressible gene expression, have been developed. However, only two markers for selecting transformants, uracil synthase (URA) and chloramphenicol acetyltransferase (CAT), are available in this alga. Therefore, manipulation of two or more different chromosomal loci in the same strain in C. merolae is limited. RESULTS: This study developed a nuclear targeting and transformant selection system using an antibiotics blasticidin S (BS) and the BS deaminase (BSD) selectable marker by homologous recombination in C. merolae. In addition, this study has succeeded in simultaneously modifying two different chromosomal loci by a single-step cotransformation based on the combination of BSD and CAT selectable markers. A C. merolae strain that expresses mitochondrion-targeted mSCARLET (with the BSD marker) and mVENUS (with the CAT marker) from different chromosomal loci was generated with this procedure. CONCLUSIONS: The newly developed BSD selectable marker enables an additional genetic modification to the already generated C. merolae transformants based on the URA or CAT system. Furthermore, the cotransformation system facilitates multiple genetic modifications. These methods and the simple nature of the C. merolae cellular and genomic architecture will facilitate studies on several phenomena common to photosynthetic eukaryotes.

Relationship between Cell Cycle and Diel Transcriptomic Changes in Metabolism in a Unicellular Red Alga.

Metabolism, cell cycle stages, and related transcriptomes in eukaryotic algae change with the diel cycle of light availability. In the unicellular red alga Cyanidioschyzon merolae, the S and M phases occur at night. To examine how diel transcriptomic changes in metabolic pathways are related to the cell cycle and to identify all genes for which mRNA levels change depending on the cell cycle, we examined diel transcriptomic changes in C. merolae In addition, we compared transcriptomic changes between the wild type and transgenic lines, in which the cell cycle was uncoupled from the diel cycle by the depletion of either cyclin-dependent kinase A or retinoblastoma-related protein. Of 4,775 nucleus-encoded genes, the mRNA levels of 1,979 genes exhibited diel transcriptomic changes in the wild type. Of these, the periodic expression patterns of 454 genes were abolished in the transgenic lines, suggesting that the expression of these genes is dependent on cell cycle progression. The periodic expression patterns of most metabolic genes, except those involved in starch degradation and de novo deoxyribonucleotide triphosphate synthesis, were not affected in the transgenic lines, indicating that the cell cycle and transcriptomic changes in most metabolic pathways are independent of the diel cycle. Approximately 40% of the cell-cycle-dependent genes were of unknown function, and approximately 19% of these genes of unknown function are shared with the green alga Chlamydomonas reinhardtii The data set presented in this study will facilitate further studies on the cell cycle and its relationship with metabolism in eukaryotic algae.

Development of a Novel Nanoarchitecture of the Robust Photosystem I from a Volcanic Microalga Cyanidioschyzon merolae on Single Layer Graphene for Improved Photocurrent Generation.

Here, we report the development of a novel photoactive biomolecular nanoarchitecture based on the genetically engineered extremophilic photosystem I (PSI) biophotocatalyst interfaced with a single layer graphene via pyrene-nitrilotriacetic acid self-assembled monolayer (SAM). For the oriented and stable immobilization of the PSI biophotocatalyst, an His6-tag was genetically engineered at the N-terminus of the stromal PsaD subunit of PSI, allowing for the preferential binding of this photoactive complex with its reducing side towards the graphene monolayer. This approach yielded a novel robust and ordered nanoarchitecture designed to generate an efficient direct electron transfer pathway between graphene, the metal redox center in the organic SAM and the photo-oxidized PSI biocatalyst. The nanosystem yielded an overall current output of 16.5 µA·cm-2 for the nickel- and 17.3 µA·cm-2 for the cobalt-based nanoassemblies, and was stable for at least 1 h of continuous standard illumination. The novel green nanosystem described in this work carries the high potential for future applications due to its robustness, highly ordered and simple architecture characterized by the high biophotocatalyst loading as well as simplicity of manufacturing.

An Autopsy Case of Pulmonary Veno-Occlusive Disease Complicated with Chronic Obstructive Pulmonary Disease and Severe Pulmonary Hypertension.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease with obstructed airflow and frequently causes secondary mild-moderate pulmonary hypertension (PH). However, a low proportion (1%-5%) of COPD patients develop severe therapy-resistant PH, and it is crucial to determine whether the patient has another disease capable of causing severe PH, including pulmonary arterial hypertension.Here, we describe a case of a 71-year-old male with COPD complicated by severe PH and right heart failure. He had a history of heavy smoking and developed progressive hypoxemia on exertion. He had severe airflow limitation (forced expiratory volume % in one second, FEV 1.0% = 42.8%) with a markedly reduced diffusing capacity of the lung (predicted diffusion capacity of carbon monoxide, %DLCO = 29%), and high-resolution computed tomography (CT) demonstrated significant lung parenchymal abnormalities such as diffuse interlobular septal thickening, ground-glass opacities, and enlarged mediastinal lymph nodes. He was diagnosed with group 3 PH caused by COPD but resistant to the treatment of COPD, diuretics, and oxygen therapy. Pathohistological analysis of autopsy specimens revealed the coexistence of interstitial fibrosis and partial occlusion of the small intrapulmonary veins, which led to a conclusive diagnosis of pulmonary veno-occlusive disease (PVOD).Because of its rarity and similarity with idiopathic pulmonary arterial hypertension, PVOD is difficult to diagnose antemortem and has a poor prognosis. High-resolution CT findings (septal thickening, ground glass, and enlarged lymph nodes) and severely reduced DLCO should be carefully evaluated for the early detection and treatment of PVOD in COPD patients with severe PH.

Acidophilic green algal genome provides insights into adaptation to an acidic environment.

Some microalgae are adapted to extremely acidic environments in which toxic metals are present at high levels. However, little is known about how acidophilic algae evolved from their respective neutrophilic ancestors by adapting to particular acidic environments. To gain insights into this issue, we determined the draft genome sequence of the acidophilic green alga Chlamydomonas eustigma and performed comparative genome and transcriptome analyses between Ceustigma and its neutrophilic relative Chlamydomonas reinhardtii The results revealed the following features in Ceustigma that probably contributed to the adaptation to an acidic environment. Genes encoding heat-shock proteins and plasma membrane H+-ATPase are highly expressed in Ceustigma This species has also lost fermentation pathways that acidify the cytosol and has acquired an energy shuttle and buffering system and arsenic detoxification genes through horizontal gene transfer. Moreover, the arsenic detoxification genes have been multiplied in the genome. These features have also been found in other acidophilic green and red algae, suggesting the existence of common mechanisms in the adaptation to acidic environments.

Glycosyltransferase MDR1 assembles a dividing ring for mitochondrial proliferation comprising polyglucan nanofilaments.

Mitochondria, which evolved from a free-living bacterial ancestor, contain their own genomes and genetic systems and are produced from preexisting mitochondria by binary division. The mitochondrion-dividing (MD) ring is the main skeletal structure of the mitochondrial division machinery. However, the assembly mechanism and molecular identity of the MD ring are unknown. Multi-omics analysis of isolated mitochondrial division machinery from the unicellular alga Cyanidioschyzon merolae revealed an uncharacterized glycosyltransferase, MITOCHONDRION-DIVIDING RING1 (MDR1), which is specifically expressed during mitochondrial division and forms a single ring at the mitochondrial division site. Nanoscale imaging using immunoelectron microscopy and componential analysis demonstrated that MDR1 is involved in MD ring formation and that the MD ring filaments are composed of glycosylated MDR1 and polymeric glucose nanofilaments. Down-regulation of MDR1 strongly interrupted mitochondrial division and obstructed MD ring assembly. Taken together, our results suggest that MDR1 mediates the synthesis of polyglucan nanofilaments that assemble to form the MD ring. Given that a homolog of MDR1 performs similar functions in chloroplast division, the establishment of MDR1 family proteins appears to have been a singular, crucial event for the emergence of endosymbiotic organelles.

Balloon Valvuloplasty to Treat Adult Symptomatic Pulmonary Valve Stenosis with Sequential Follow-Up Using Cardiac Magnetic Resonance Imaging in Combination with Echocardiography.

Pulmonary valve stenosis (PVS) accounts for approximately 10% of all congenital heart defects. Echocardiography and right heart catheterization are the gold standards for diagnosis of PVS and for assessing disease severity and responsiveness to treatment.Recently, cardiac magnetic resonance imaging (cMRI) has been established as an important tool to comprehensively evaluate cardiac structure and function; however, research into the usefulness of cMRI for PVS management is limited. Here, we describe a case of a 59-year-old female with isolated, severe PVS who was successfully treated with balloon pulmonary valvuloplasty (BPV) followed by sequential cMRI at 1 and 12 months. Exertional dyspnea and elevated plasma BNP concentration were observed 1 month after BPV; however, echocardiographic findings did not indicate recurrent stenosis or increased pulmonary valve regurgitation but an increase in mitral E/e'. cMRI demonstrated improved systolic forward flow and RV function with enlargement of LV volume, and the rapid increase in LV preload might be associated with the transient deterioration in symptoms and BNP level, which both gradually improved within 3 months after BPV. cMRI further depicted that a reduced RV mass index and increased RV cardiac output were achieved gradually during the follow-up period.In conclusion, cMRI in combination with echocardiography was sufficiently informative to follow-up this PVS patient both before and after BPV. cMRI is easily reproducible in adult patients; therefore, cMRI should be recommended for long-term follow-up in adult PVS patients.

Effect of Treatment by Female Cardiologists on Short-Term Readmission Rates of Patients Hospitalized With Cardiovascular Diseases.

BACKGROUND: The effect of the sex ratio of the team of the attending doctors on clinical outcomes remains unknown.Methods and Results:This retrospective cohort study included 9,544 patients admitted between 2012 and 2018 for cardiovascular diseases. They were treated by teams of 3 attending doctors comprising a trainee doctor, middle-grade cardiologist who played the main role in the clinical management, and upper-grade cardiologist who was responsible for the management. We explored whether the sex of the attending doctors influenced the risk of emergency readmission within 30 days after discharge. The primary hospitalization periods were similar for male and female middle-grade cardiologists. The risk of emergency readmission of patients hospitalized with cardiovascular diseases was significantly higher for patients treated by male middle-grade cardiologists than in those treated by female middle-grade cardiologists (odds ratio: 2.09, P<0.01). This beneficial effect of treatment by female cardiologists was observed in younger (<65 years) patients, male patients, patients with New York Heart Association stages II-IV, and those with emergency primary hospitalization, and in medical teams led by a male upper-grade cardiologist. CONCLUSIONS: The risk of emergency readmission after discharge in patients hospitalized with cardiovascular diseases was ameliorated when treatment was performed by female middle-grade cardiologists. The combination of male and female cardiologists in the attending doctors' team could result in better prognoses for cardiovascular patients.

Correction to: The potential of cardiac rehabilitation as a method of suppressing abdominal aortic aneurysm expansion: a pilot study.

In the original publication of the article, under the result section.

The potential of cardiac rehabilitation as a method of suppressing abdominal aortic aneurysm expansion: a pilot study.

This study is a prospective evaluation of the effectiveness of cardiac rehabilitation (CR) in terms of clinical outcomes for small abdominal aortic aneurysms (AAA) that were previously reported in a retrospective cohort study. We conducted a prospective non-randomized trial on patients with small AAA (N = 40; mean age 75.0 ± 6.6 years). Patients were enrolled into one of two groups, rehabilitation (CR) or non-rehabilitation (non-CR) group. Only CR group participated in a supervised-CR program including bicycle ergometer for 150 days. The AAA expansion rate and the risk of AAA repair were compared between two groups. We also researched the relationship between AAA expansion rate and body composition, blood IL-6 and TGFß1 levels. The CR (N = 15) and non-CR groups (N = 25) were comparable in terms their baseline data. The CR group had a significantly smaller change in the maximal AAA size (- 1.3 ± 2.4 mm/years) compared to the non-CR group (2.0 ± 3.6 mm/years) (p < 0.01). The IL-6, and TGFß1 levels were unrelated to the changes in AAA size. There was mild positive correlation between the change in systolic blood pressure from rest to exercise and the AAA expansion rate (p = 0.06). The risk of AAA repair after 12 months was lower in the CR group compared to the non-CR group (0% vs. 28%, respectively). CR in patients with small AAA significantly suppressed AAA expansion and resulted in a lowered risk of AAA repair.Clinical trial Trial name: The study of the profitability and protective effect of cardiac rehabilitation on abdominal aortic aneurysm. Number: UMIN000028237. UTL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R0000323.

Chloroplast division checkpoint in eukaryotic algae.

Chloroplasts evolved from a cyanobacterial endosymbiont. It is believed that the synchronization of endosymbiotic and host cell division, as is commonly seen in existing algae, was a critical step in establishing the permanent organelle. Algal cells typically contain one or only a small number of chloroplasts that divide once per host cell cycle. This division is based partly on the S-phase-specific expression of nucleus-encoded proteins that constitute the chloroplast-division machinery. In this study, using the red alga Cyanidioschyzon merolae, we show that cell-cycle progression is arrested at the prophase when chloroplast division is blocked before the formation of the chloroplast-division machinery by the overexpression of Filamenting temperature-sensitive (Fts) Z2-1 (Fts72-1), but the cell cycle progresses when chloroplast division is blocked during division-site constriction by the overexpression of either FtsZ2-1 or a dominant-negative form of dynamin-related protein 5B (DRP5B). In the cells arrested in the prophase, the increase in the cyclin B level and the migration of cyclin-dependent kinase B (CDKB) were blocked. These results suggest that chloroplast division restricts host cell-cycle progression so that the cell cycle progresses to the metaphase only when chloroplast division has commenced. Thus, chloroplast division and host cell-cycle progression are synchronized by an interactive restriction that takes place between the nucleus and the chloroplast. In addition, we observed a similar pattern of cell-cycle arrest upon the blockage of chloroplast division in the glaucophyte alga Cyanophora paradoxa, raising the possibility that the chloroplast division checkpoint contributed to the establishment of the permanent organelle.

Comparison of range of motion during movement from supine to sitting position in healthy young and elderly participants.

[Purpose] The purpose of this study was to compare the range of motion (ROM) during supine-to-sitting position (StSP) movement between healthy young and elderly participants to understand age-related tendencies, which is beneficial for the assessment and treatment of frail elderly. [Participants and Methods] The participants were 14 healthy young males (age, 19-24 years) and 16 healthy elderly individuals (8 males and 8 females; age, 65-74 years). Rising movement was performed 5 times freely at a comfortable speed. [Results] The joint angles during StSP movements in right shoulder abduction, extension of both shoulder joints, right elbow flexion, trunk extension, and adduction of both hip joints were significantly larger, whereas neck flexion, trunk flexion, and left hip joint abduction were significantly smaller in the healthy elderly participants than in the healthy young participants. All joint movements were earlier in the elderly participants than in the healthy young participants. [Conclusion] The results of this study suggest that focusing on how to use both upper limbs is important, in addition to the neck and trunk, when evaluating StSP movement. Similarly, to encourage independence during StSP movement, the elbow extensors must be strengthened.

Multistep thermal decomposition of granular sodium perborate tetrahydrate: a kinetic approach to complex reactions in solid-gas systems.

This article demonstrates a kinetic approach to partially overlapping multistep chemical reactions in solid-gas systems as exemplified by the thermal decomposition of granular sodium perborate tetrahydrate. This reaction proceeds via successive thermal dehydration and decomposition occurring at different temperatures to form sodium metaborate. Each reaction process comprises several kinetic steps originating from different physicochemical and physico-geometric phenomena. The partially overlapping multistep processes were characterized using available thermoanalytical techniques and microscopic observations. Conventional isoconversional kinetic analysis and empirical mathematical deconvolution were applied to each reaction process as preliminary kinetic approaches to extracting provable kinetic information. Then, each reaction process was analyzed kinetically based on a cumulative kinetic equation, i.e., kinetic deconvolution analysis. The results of the kinetic deconvolution analysis were further examined by comparison with other kinetic information for the specific kinetic steps obtained from different thermoanalytical measurements. From the results of this comprehensive kinetic approach, the kinetic features of the thermal dehydration and decomposition processes were revealed by identifying their contributing physicochemical and physico-geometric phenomena and evaluating their influences on the overall multistep processes.

Correction to: High-intensity aerobic interval training can lead to improvement in skeletal muscle power among in-hospital patients with advanced heart failure.

In the original publication of the article, the unit of hand in Fig. 2 was wrongly given as "N/kg" instead of "kg".

High-intensity aerobic interval training can lead to improvement in skeletal muscle power among in-hospital patients with advanced heart failure.

This study investigated the effectiveness and safety of interval training during in-hospital treatment of patients with advanced heart failure. Twenty-four consecutive patients with advanced symptomatic heart failure who were referred for cardiac transplant evaluation were recruited. After performing aerobic exercise for approximate intensity, high-intensity interval training (HIIT) was performed. The protocol consisted of 3 or 4 sessions of 1-min high-intensity exercise aimed at 80% of peak VO2 or 80% heart rate reserve, followed by 4-min recovery periods of low intensity. In addition to the necessary laboratory data, hand grip strength and knee extensor strength were evaluated at the start of exercise training and both at the start and the end of HIIT. Knee extensor strength was standardized by body weight. The BNP level at the start of exercise training was 432 (812) pg/mL and it significantly decreased to 254 (400) pg/mL (p < 0.001) at the end of HIIT. Hand grip strength did not change during course. By contrast, knee extensor strength significantly increased during HIIT [4.42 ± 1.43 â†’ 5.28 ± 1.45 N/kg, p < 0.001], whereas the improvement of knee extensor strength was not significant from the start of exercise training to the start of HIIT. In addition, the change in knee extensor strength during HIIT was significantly associated with the hemoglobin A1c level at the start of exercise (R = - 0.55; p = 0.015). HIIT has a positive impact on skeletal muscle strength among in-hospital patients with advanced heart failure.