Evaluating haemodynamic changes: vericiguat in patients with heart failure with reduced ejection fraction.

AIMS: Vericiguat has been used to treat patients with heart failure with reduced ejection fraction (HFrEF) who demonstrated worsening heart failure despite treatment with other guideline-directed medical therapies. The haemodynamic effects of vericiguat remain unclear. METHODS AND RESULTS: This study enrolled 12 patients (median age, 63 [quartiles 53.5, 70] years; 16.7%(N=2) women) with symptomatic HFrEF (New York Heart Association functional class II-IV) who demonstrated worsening heart failure despite treatment with the four foundational guideline-recommended therapies between March and December 2022, with follow-ups completed in June 2023. A balloon-tipped pulmonary artery thermodilution catheter was placed in the right internal jugular vein to perform right heart catheterisation (RHC) on day 1. Haemodynamic data were acquired before and after vericiguat intake (2.5 mg) on days 2 and 3. The data on days 2 and 3 were averaged. RHC was repeated on day 105 (37, 168). Oral intake of vericiguat 2.5 mg decreased mean pulmonary artery pressure (19.3 [14.3, 26.8] mmHg) and pulmonary artery wedge pressure (PAWP) (11 [7.5, 15] mmHg) before the intake to mean pulmonary artery pressure (17.5 [12.5, 24] mmHg) and PAWP (9.3 [6.8, 14] mmHg) at 30 min after (both P < 0.05). Reduction in PAWP was also found from 14.5 [9.5, 19.5] mmHg on day 1 to 9.5 [6.5, 12.5] mmHg on day 105 (37, 168) (P < 0.05), when vericiguat was titrated to 2.5 mg 25% (N = 3), 5 mg 50% (N = 6), and 10 mg 25% (N = 3). CONCLUSIONS: The consistent reduction in PAWP underscores the well-tolerated nature of vericiguat and its potential to enhance cardiac performance in patients with HFrEF.

Machine learning-based computer-aided simple triage (CAST) for COVID-19 pneumonia as compared with triage by board-certified chest radiologists.

PURPOSE: Several reporting systems have been proposed for providing standardized language and diagnostic categories aiming for expressing the likelihood that lung abnormalities on CT images represent COVID-19. We developed a machine learning (ML)-based CT texture analysis software for simple triage based on the RSNA Expert Consensus Statement system. The purpose of this study was to conduct a multi-center and multi-reader study to determine the capability of ML-based computer-aided simple triage (CAST) software based on RSNA expert consensus statements for diagnosis of COVID-19 pneumonia. METHODS: For this multi-center study, 174 cases who had undergone CT and polymerase chain reaction (PCR) tests for COVID-19 were retrospectively included. Their CT data were then assessed by CAST and consensus from three board-certified chest radiologists, after which all cases were classified as either positive or negative. Diagnostic performance was then compared by McNemar's test. To determine radiological finding evaluation capability of CAST, three other board-certified chest radiologists assessed CAST results for radiological findings into five criteria. Finally, accuracies of all radiological evaluations were compared by McNemar's test. RESULTS: A comparison of diagnosis for COVID-19 pneumonia based on RT-PCR results for cases with COVID-19 pneumonia findings on CT showed no significant difference of diagnostic performance between ML-based CAST software and consensus evaluation (p > 0.05). Comparison of agreement on accuracy for all radiological finding evaluations showed that emphysema evaluation accuracy for investigator A (AC = 91.7%) was significantly lower than that for investigators B (100%, p = 0.0009) and C (100%, p = 0.0009). CONCLUSION: This multi-center study shows COVID-19 pneumonia triage by CAST can be considered at least as valid as that by chest expert radiologists and may be capable for playing as useful a complementary role for management of suspected COVID-19 pneumonia patients as well as the RT-PCR test in routine clinical practice.

Targeting acidic pre-metastatic niche in lungs by pH low insertion peptide and its utility for anti-metastatic therapy.

Dysregulated extracellular pH, the universal feature of tumor, works as an evolutional force to drive dissemination of tumor cells. It is well-established that tumor acidity is associated with tumor growth and metastasis. However, the pH of pre-metastatic niche remains unclear. We hypothesized that primary tumor cells remotely prime acidity in secondary organ to achieve metastatic colonization. Herein, we demonstrated that the pH responsive probe pH Low Insertion Peptide (pHLIP) was notably accumulated in pre-metastatic lungs of 4T1.2 breast tumor-bearing mice. The pHLIP-targeted lungs showed high amounts of lactate and overexpressed glycolysis-related proteins. Pharmacological inhibition of glycolysis suppressed the lung acidification induced by 4T1.2 cancer cell culture supernatant and delayed subsequent metastatic burden of disseminated tumor cells. In the acidic lungs, pHLIP was primarily localized in alveolar type 2 cells which strongly expressed glycolysis-related proteins. 4T1.2-derived extracellular vesicles expressed some of the glycolysis-related proteins, and their administration increased pHLIP accumulation and glycolytic enhancement in lungs. pHLIP-conjugated dexamethasone effectively attenuated lung metastatic burden by disrupting pro-inflammatory response in the acidic lungs. From these results, targeting the metastasis-supporting microenvironment by pHLIP technology creates possibility to identify pre-metastatic organ and prevent metastatic recurrence.

Intractable Ventricular Tachycardia Prior to an Overt Cardiac Tumor Mass of Metastatic Cardiac Rhabdomyosarcoma (Spindle-cell Type).

We herein report a 37-year-old man who experienced recurrence of metastatic cardiac rhabdomyosarcoma along with intractable ventricular tachycardia (VT) 7 years after resection of rhabdomyosarcoma in his right elbow. At 36 years old, he developed VT unresponsive to radiofrequency catheter ablation (RFCA). Initially, the cardiac tumor was not detected, but it gradually grew in size at the RFCA site. A surgical biopsy confirmed the diagnosis of metastatic cardiac rhabdomyosarcoma. Despite radiation therapy, cardiac tumor progression and VT instability could not be prevented. Ultimately, the patient died 27 months after the initial documentation of VT.

Inhaled nitric oxide testing in predicting prognosis in pulmonary hypertension due to left-sided heart diseases.

AIMS: The pathophysiology of pulmonary hypertension (PH) due to left-sided heart disease (Group 2 PH) is distinct from that of other groups of PH, yet there are still no approved therapies that selectively target pulmonary circulation. The increase in pulmonary capillary pressure due to left-sided heart disease is a trigger event for physical and biological alterations of the pulmonary circulation, including the nitric oxide (NO)-soluble guanylate cyclase-cyclic guanosine monophosphate axis. This study investigated inhaled NO vasoreactivity tests for patients with Group 2 PH and hypothesized that these changes may have a prognostic impact. METHODS AND RESULTS: This was a single-centre, retrospective study with a median follow-up of 365 days. From January 2011 to December 2015, we studied 69 patients with Group 2 PH [age, 61.5 ± 13.0 (standard deviation) years; male:female, 49:20; left ventricular ejection fraction, 50.1 ± 20.4%; mean pulmonary arterial pressure, ≥25 mmHg; and pulmonary arterial wedge pressure (PAWP), >15 mmHg]. No adverse events were observed after NO inhalation. Thirty-four patients with Group 2 PH showed increased PAWP (ΔPAWP: 3.26 ± 2.22 mmHg), while the remaining 35 patients did not (ΔPAWP: -2.11 ± 2.29 mmHg). Multivariate analysis revealed that increased PAWP was the only significant predictor of all-cause death or hospitalization for heart failure (HF) after 1 year (hazard ratio 4.35; 95% confidence interval, 1.27-14.83; P = 0.019). The acute response of PAWP to NO differed between HF with preserved and reduced ejection fractions. CONCLUSIONS: Patients with Group 2 PH were tolerant of the inhaled NO test. NO-induced PAWP is a novel prognostic indicator.

Beneficial Effects of Low-Intensity Pulsed Ultrasound Therapy on Right Ventricular Dysfunction in Animal Models.

Right ventricular failure (RVF) is a leading cause of death in patients with pulmonary hypertension; however, effective treatment remains to be developed. We have developed low-intensity pulsed ultrasound therapy for cardiovascular diseases. In this study, we demonstrated that the expression of endothelial nitric oxide synthase (eNOS) in RVF patients was downregulated and that eNOS expression and its downstream pathway were ameliorated through eNOS activation in 2 animal models of RVF. These results indicate that eNOS is an important therapeutic target of RVF, for which low-intensity pulsed ultrasound therapy is a promising therapy for patients with RVF.

Mitochondrial connexin43 and mitochondrial KATP channels modulate triggered arrhythmias in mouse ventricular muscle.

Connexin43 (Cx43) exits as hemichannels in the inner mitochondrial membrane. We examined how mitochondrial Cx43 and mitochondrial KATP channels affect the occurrence of triggered arrhythmias. To generate cardiac-specific Cx43-deficient (cCx43-/-) mice, Cx43flox/flox mice were crossed with α-MHC (Myh6)-cre+/- mice. The resulting offspring, Cx43flox/flox/Myh6-cre+/- mice (cCx43-/- mice) and their littermates (cCx43+/+ mice), were used. Trabeculae were dissected from the right ventricles of mouse hearts. Cardiomyocytes were enzymatically isolated from the ventricles of mouse hearts. Force was measured with a strain gauge in trabeculae (22°C). To assess arrhythmia susceptibility, the minimal extracellular Ca2+ concentration ([Ca2+]o,min), at which arrhythmias were induced by electrical stimulation, was determined in trabeculae. ROS production was estimated with 2',7'-dichlorofluorescein (DCF), mitochondrial membrane potential with tetramethylrhodamine methyl ester (TMRM), and Ca2+ spark frequency with fluo-4 and confocal microscopy in cardiomyocytes. ROS production within the mitochondria was estimated with MitoSoxRed and mitochondrial Ca2+ with rhod-2 in trabeculae. Diazoxide was used to activate mitochondrial KATP. Most of cCx43-/- mice died suddenly within 8 weeks. Cx43 was present in the inner mitochondrial membrane in cCx43+/+ mice but not in cCx43-/- mice. In cCx43-/- mice, the [Ca2+]o,min was lower, and Ca2+ spark frequency, the slope of DCF fluorescence intensity, MitoSoxRed fluorescence, and rhod-2 fluorescence were higher. TMRM fluorescence was more decreased in cCx43-/- mice. Most of these changes were suppressed by diazoxide. In addition, in cCx43-/- mice, antioxidant peptide SS-31 and N-acetyl-L-cysteine increased the [Ca2+]o,min. These results suggest that Cx43 deficiency activates Ca2+ leak from the SR, probably due to depolarization of mitochondrial membrane potential, an increase in mitochondrial Ca2+, and an increase in ROS production, thereby causing triggered arrhythmias, and that Cx43 hemichannel deficiency may be compensated by activation of mitochondrial KATP channels in mouse hearts.

Association Between Changes in Alcohol Consumption Before and After the Great East Japan Earthquake and Risk of Hypertension: A Study Using the Ministry of Health, Labour and Welfare National Database.

BACKGROUND: The 2011 Great East Japan Earthquake has resulted in a nuclear accident, forcing residents of the surrounding areas to evacuate. To determine any association between excessive drinking and hypertension in the setting of disaster, we assessed whether the proportion of excessive drinkers increased and if post-disaster excessive drinking was a risk factor for hypertension. METHODS: This retrospective study assessed data from the Japanese National Database. Cumulative population data for Fukushima Prefecture (3,497,576 people) were analyzed by categorizing residents into four areas-evacuation, coastal, central, and mountainous-to calculate the proportion of excessive, heavy (equivalent to binge drinking), and at-risk drinkers for 2008-2017. The hazard ratios (HRs) for the incidence of hypertension for 2012-2017 were examined in association with changes in drinking status pre- and post-disaster, which included 136,404 people who received specific health checkups pre-disaster (2008-2010) and post-disaster (2011-2012). RESULTS: The proportion of excessive drinkers among women increased after the disaster in all areas examined. The association between excessive drinking and the incidence of hypertension was determined among men and women in all areas; it was stronger among women in the evacuation areas, with the sex- and age-adjusted HRs for the incidence of hypertension of 1.41 for pre-disaster excessive drinking, 2.34 for post-disaster excessive drinking, and 3.98 for pre- and post-disaster excessive drinking, compared with not excessive drinking pre- and post-disaster. CONCLUSION: Excessive drinking post-disaster may be associated with an increased risk of hypertension among men and women, especially among women in the evacuation areas.

Adult-onset Leigh Syndrome with a m.9176T>C Mutation Manifested As Reversible Cerebral Vasoconstriction Syndrome.

A 26-year-old woman developed a sudden headache, ptosis, and diplopia. Magnetic resonance imaging and angiography demonstrated a symmetrical lesion from the midbrain to the brainstem, involving the solitary nucleus and multifocal cerebral artery narrowing. Reversible cerebral vasoconstriction syndrome (RCVS) was suspected, and the patient improved after vasodilatation. Leigh syndrome was suspected due to the elevated serum pyruvate level, so mitochondrial DNA was analyzed, and an m.9176T>C mutation was detected. The final diagnosis was adult-onset Leigh syndrome manifesting as RCVS. An uncontrolled baroreflex due to a solitary nuclear lesion or endothelial dysfunction may have contributed to her unique presentation.

Usefulness of cardiac magnetic resonance for early detection of cancer therapeutics-related cardiac dysfunction in breast cancer patients.

BACKGROUND: Prognosis of breast cancer patients has been improved along with the progress in cancer therapies. However, cancer therapeutics-related cardiac dysfunction (CTRCD) has been an emerging issue. For early detection of CTRCD, we examined whether native T1 mapping and global longitudinal strain (GLS) using cardiac magnetic resonance (CMR) and biomarkers analysis are useful. METHODS: We prospectively enrolled 83 consecutive chemotherapy-naïve female patients with breast cancer (mean age, 56 ± 13 yrs.) between 2017 and 2020. CTRCD was defined based on echocardiography as left ventricular ejection fraction (LVEF) below 53% at any follow-up period with LVEF>10% points decrease from baseline after chemotherapy. To evaluate cardiac function, CMR (at baseline and 6 months), 12­lead ECG, echocardiography, and biomarkers (at baseline and every 3 months) were evaluated. RESULTS: A total of 164 CMRs were performed in 83 patients. LVEF and GLS were significantly decreased after chemotherapy (LVEF, from 71.2 ± 4.4 to 67.6 ± 5.8%; GLS, from -27.9 ± 3.9 to -24.7 ± 3.5%, respectively, both P < 0.01). Native T1 value also significantly elevated after chemotherapy (from 1283 ± 36 to 1308 ± 39 msec, P < 0.01). Among the 83 patients, 7 (8.4%) developed CTRCD. Of note, native T1 value before chemotherapy was significantly higher in patients with CTRCD than in those without it (1352 ± 29 vs. 1278 ± 30 msec, P < 0.01). The multivariable logistic regression analysis revealed that native T1 value was an independent predictive factor for the development of CTRCD [OR 2.33; 95%CI 1.15-4.75, P = 0.02]. CONCLUSIONS: These results indicate that CMR is useful to detect chemotherapy-related myocardial damage and predict for the development of CTRCD in breast cancer patients.

Complete Genome Sequences of Grapevine Red Globe Virus in Japan.

Two complete and three partial genome sequences of grapevine red globe virus (GRGV) from grapevines (Vitis spp.) in Japan were determined.

Systemic-pulmonary collateral supply associated with clinical severity of chronic thromboembolic pulmonary hypertension: a study using intra-aortic computed tomography angiography.

OBJECTIVES: To assess whether systemic-pulmonary collaterals are associated with clinical severity and extent of pulmonary perfusion defects in chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: This prospective study was approved by a local ethics committee. Twenty-four patients diagnosed with inoperable CTEPH were enrolled between July 2014 and February 2017. Systemic-pulmonary collaterals were detected using pulmonary vascular enhancement on intra-aortic computed tomography (CT) angiography. The pulmonary enhancement parameters were calculated, including (1) Hounsfield unit differences (HUdiff) between pulmonary trunks and pulmonary arteries (PAs) or veins (PVs), namely HUdiff-PA and HUdiff-PV, on the segmental base; (2) the mean HUdiff-PA, mean HUdiff-PV, numbers of significantly enhanced PAs and PVs, on the patient base. Pulmonary perfusion defects were recorded and scored using the lung perfused blood volume (PBV) based on intravenous dual-energy CT (DECT) angiography. Pearson's or Spearman's correlation coefficients were used to evaluate correlations between the following: (1) segment-based intra-aortic CT and intravenous DECT parameters (2) patient-based intra-aortic CT parameters and clinical severity parameters or lung PBV scores. Statistical significance was set at p < 0.05. RESULTS: Segmental HUdiff-PV was correlated with the segmental perfusion defect score (r = 0.45, p < 0.01). The mean HUdiff-PV was correlated with the mean pulmonary arterial pressure (PAP) (r = 0.52, p < 0.01), cardiac output (rho = - 0.41, p = 0.05), and lung PBV score (rho = 0.43, p = 0.04). And the number of significantly enhanced PVs was correlated with the mean PAP (r = 0.54, p < 0.01), pulmonary vascular resistance (r = 0.54, p < 0.01), and lung PBV score (rho = 0.50, p = 0.01). CONCLUSIONS: PV enhancement measured by intra-aortic CT angiography reflects clinical severity and pulmonary perfusion defects in CTEPH. KEY POINTS: • Intra-aortic CT angiography demonstrated heterogeneous enhancement within the pulmonary vasculature, showing collaterals from the systemic arteries to the pulmonary circulation in CTEPH. • The degree of systemic-pulmonary collateral development was significantly correlated with the clinical severity of CTEPH and may be used to evaluate disease progression. • The distribution of systemic-pulmonary collaterals is positively correlated with perfusion defects in the lung segments in CTEPH.

Thalamocortical axons control the cytoarchitecture of neocortical layers by area-specific supply of VGF.

Neuronal abundance and thickness of each cortical layer are specific to each area, but how this fundamental feature arises during development remains poorly understood. While some of area-specific features are controlled by intrinsic cues such as morphogens and transcription factors, the exact influence and mechanisms of action by cues extrinsic to the cortex, in particular the thalamic axons, have not been fully established. Here, we identify a thalamus-derived factor, VGF, which is indispensable for thalamocortical axons to maintain the proper amount of layer 4 neurons in the mouse sensory cortices. This process is prerequisite for further maturation of the primary somatosensory area, such as barrel field formation instructed by a neuronal activity-dependent mechanism. Our results provide an actual case in which highly site-specific axon projection confers further regional complexity upon the target field through locally secreting signaling molecules from axon terminals.

Quantification of vortex flow in pulmonary arteries of patients with chronic thromboembolic pulmonary hypertension.

PURPOSE: This study proposes an objective method of quantifying the vortex flow in pulmonary arteries to compare the duration of its presence before and after balloon pulmonary angioplasty (BPA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: Thoracic 4D-flow magnetic resonance imaging was performed in 28 CTEPH patients before and after BPA. Planes were set in pulmonary arteries to evaluate volume flow rate (VFR), the duration, and area of backward flow in the pulmonary trunk, which is a component of the vortex flow. The full width at half maximum (FWHM) of the peak of the time course of VFR of backward flow was assessed to quantify the duration of the vortical flow. RESULTS: Although overall flow patterns after BPA appeared to be the same as the one before BPA, significant decreases in the FWHM, area, and VFR of the backward flow after BPA were found (FWHM: before, 1.88 × 10-1 ± 1.51 × 10-2 [cardiac cycle] vs. after, 1.65 × 10-1 ± 1.86 × 10-2 [cardiac cycle]; area ratio: before, 2.67 × 10-1 ± 1.30 × 10-2 vs. after, 2.38 × 10-1 ± 1.31 × 10-2; VFR: before, 13.6 ± 2.21 [mL/s] vs. after, 11.3 ± 2.36 [mL/s]). CONCLUSION: BPA promoted significant decreases in the FWHM, area, and VFR of backward flow in the pulmonary trunk, thereby facilitating efficient blood transport. The tendencies for these changes were to be larger for cases where BPA more greatly decreased the pressure. The results suggest that the FWHM, area, and VFR are useful indicators for the noninvasive evaluation of the therapeutic effects of BPA.

Roles of stretch-activated channels and NADPH oxidase 2 in the induction of twitch contraction by muscle stretching in rat ventricular muscle.

Mechano-electric feedback means that muscle stretching causes depolarization of membrane potential. We investigated whether muscle stretching induces action potential and twitch contraction with a threshold of sarcomere length (SL) and what roles stretch-activated channels (SACs) and stretch-activated NADPH oxidase (X-ROS signaling) play in the induction. Trabeculae were obtained from the right ventricles of rat hearts. Force, SL, and [Ca2+]i were measured. Various degrees of stretching from the SL of 2.0 µm were applied 0.5 s after the last stimulus of the electrical train with 0.4-s intervals for 7.5 s. The SLtwitch was defined as the minimal SL at which twitch contraction was induced by the stretching. Muscle stretching induced twitch contraction with a threshold of SL at 0.4-s stimulus intervals ([Ca2+]o = 0.7 mmol/L). The SLtwitch was not changed by increasing the stimulus intervals and [Ca2+]o and by adding 1 µmol/L isoproterenol. The SLtwitch was not changed by adding 10 µmol/L Gd3+, 100 µmol/L or 200 µmol/L streptomycin, and 5 µmol/L GsMTx4. The SLtwitch was not changed by adding 1 µmol/L ryanodine and 3 µmol/L diphenyleneiodonium chloride. In contrast, the SLtwitch was increased by elevating extracellular K+ from 5 to 10 mmol/L and by adding the stretching during the refractory period of membrane potential. The addition of the stretching-induced twitch contraction more frequently induced arrhythmias. These results suggest that muscle stretching can induce twitch contraction with a threshold of SL and concern the occurrence of arrhythmias and that SACs and X-ROS signaling play no roles in the induction.

Oxidized Phospholipids and Neutrophil Elastase Coordinately Play Critical Roles in NET Formation.

Neutrophil extracellular traps (NETs) are web-like structures consisting of decondensed chromatin DNA and contents of granules, such as myeloperoxidase (MPO) and neutrophil elastase (NE). NETs are usually released from neutrophils undergoing NETosis, a neutrophil-specific cell death mode characterized by the collapse and disappearance of cell membranes and nuclear envelopes. It is well known that production of reactive oxygen species (ROS) triggers NETosis and NET formation. However, details of intracellular signaling downstream of ROS production during NETosis and NET formation remains uncertain. Here, we demonstrated that the peroxidation of phospholipids plays a critical role in NETosis and NET formation induced by phorbol 12-myristate13-acetate (PMA) or immune complex in vitro and by lipopolysaccharide (LPS) in vivo. This phospholipid peroxidation is mediated by the enzymatic activity of MPO. On the other hand, NE, which was previously reported to be released from granules to cytosol by MPO during NET formation, is not required for either the peroxidation of phospholipids or the execution of NETosis, but contributes to chromatin decondensation and nuclear swelling independently of MPO-mediated oxidized phospholipids. Analysis of isolated nuclei clearly demonstrated that oxidized phospholipids and NE differently yet synergistically execute chromatin decondensation and nuclear swelling, and the subsequent release of nuclear contents. These findings indicate the dual roles of MPO in NETosis and NET formation, and provide new insight into the molecular mechanism of these phenomena.