These results indicate that BPA improves haemodynamics and exercise capacity in inoperable CTEPH patients with acceptable complication rate and that the beneficial haemodynamic effects of BPA persist for years with resultant good long-term prognosis.

The mammalian neocortex is composed of various types of neurons that reflect its laminar and area structures. It has been suggested that not only intrinsic but also afferent-derived extrinsic factors are involved in neuronal differentiation during development. However, the role and molecular mechanism of such extrinsic factors are almost unknown. Here, we attempted to identify molecules that are expressed in the thalamus and affect cortical cell development. First, thalamus-specific molecules were sought by comparing gene expression profiles of the developing rat thalamus and cortex using microarrays, and by constructing a thalamus-enriched subtraction cDNA library. A systematic screening by in situ hybridization showed that several genes encoding extracellular molecules were strongly expressed in sensory thalamic nuclei. Exogenous and endogenous protein localization further demonstrated that two extracellular molecules, Neuritin-1 (NRN1) and VGF, were transported to thalamic axon terminals. Application of NRN1 and VGF to dissociated cell culture promoted the dendritic growth. An organotypic slice culture experiment further showed that the number of primary dendrites in multipolar stellate neurons increased in response to NRN1 and VGF, whereas dendritic growth of pyramidal neurons was not promoted. These molecules also increased neuronal survival of multipolar neurons. Taken together, these results suggest that the thalamus-specific molecules NRN1 and VGF play an important role in the dendritic growth and survival of cortical neurons in a cell type-specific manner.

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The UNC-5 family of netrin receptors is known to regulate axon guidance, cell migration, and cell survival. We have previously demonstrated that unc5d, one of the UNC-5 family member genes, is specifically expressed in layer 4 of the developing rat neocortex (Zhong Y, Takemoto M, Fukuda T, Hattori Y, Murakami F, Nakajima D, Nakayama M, Yamamoto N. 2004. Identification of the genes that are expressed in the upper layers of the neocortex. Cereb Cortex. 14:1144-1152). However, the role of UNC5D in cortical development is still unknown. In this study, we revealed that unc5d was highly expressed in the primary sensory areas of the mouse neocortex at around postnatal day 7. Netrin-4 was also found to be predominantly expressed in layer 4 of the sensory cortex and sensory thalamic nuclei. Cell surface binding assay showed that netrin-4 protein bound to UNC5D-expressing cells. An in vitro study further demonstrated that cell death of unc5d-expressing layer 4 cells was reduced by exogenous application of netrin-4 protein, whereas UNC5D is not sufficient to mediate the effect of netrin-4 in deep layer cells. Taken together, these results suggest that UNC5D is primarily expressed by layer 4 cells in the primary sensory areas of the developing neocortex and may mediate the effect of netrin-4 on cortical cell survival in a lamina-specific manner.

The period following heart failure hospitalization (HFH) is a vulnerable time with high rates of death or recurrent HFH.OBJECTIVE To evaluate clinical characteristics, outcomes, and treatment response to vericiguat according to prespecified index event subgroups and time from index HFH in the Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA) trial. DESIGN, SETTING, AND PARTICIPANTSAnalysis of an international, randomized, placebo-controlled trial. All VICTORIA patients had recent (<6 months) worsening HF (ejection fraction <45%). Index event subgroups were less than 3 months after HFH (n = 3378), 3 to 6 months after HFH (n = 871), and those requiring outpatient intravenous diuretic therapy only for worsening HF (without HFH) in the previous 3 months (n = 801). Data were analyzed between May 2, 2020, and May 9, 2020.INTERVENTION Vericiguat titrated to 10 mg daily vs placebo. MAIN OUTCOMES AND MEASURESThe primary outcome was time to a composite of HFH or cardiovascular death; secondary outcomes were time to HFH, cardiovascular death, a composite of all-cause mortality or HFH, all-cause death, and total HFH. RESULTS Among 5050 patients in the VICTORIA trial, mean age was 67 years, 24% were women, 64% were White, 22% were Asian, and 5% were Black. Baseline characteristics were balanced between treatment arms within each subgroup. Over a median follow-up of 10.8 months, the primary event rates were 40.9, 29.6, and 23.4 events per 100 patient-years in the HFH at less than 3 months, HFH 3 to 6 months, and outpatient worsening subgroups, respectively. Compared with the outpatient worsening subgroup, the multivariable-adjusted relative risk of the primary outcome was higher in HFH less than 3 months (adjusted hazard ratio, 1.48; 95% CI, 1.27-1.73), with a time-dependent gradient of risk demonstrating that patients closest to their index HFH had the highest risk. Vericiguat was associated with reduced risk of the primary outcome overall and in all subgroups, without evidence of treatment heterogeneity. Similar results were evident for all-cause death and HFH. Addtionally, a continuous association between time from HFH and vericiguat treatment showed a trend toward greater benefit with longer duration since HFH. Safety events (symptomatic hypotension and syncope) were infrequent in all subgroups, with no difference between treatment arms.CONCLUSIONS AND RELEVANCE Among patients with worsening chronic HF, those in closest proximity to their index HFH had the highest risk of cardiovascular death or HFH, irrespective of age or clinical risk factors. The benefit of vericiguat did not differ significantly across the spectrum of risk in worsening HF.

In CTEPH, RV pressure overload causes RV dysfunction and dilation with resulting poor prognosis. 13-15 Precise evaluation of RV function, however, still remains difficult because of anatomical complexity of the RV chamber. Recently, cardiac magnetic resonance imaging (CMR) has been widely used to evaluate RV configuration and function because it non-invasively provides 3-D RV imaging, high-resolution evaluation of RV structure and accurate functional assessment without geometric assumptions. 16 Kreitner et al used CMR to evaluate change in cardiac function and pulmonary flow after PEA in CTEPH patients. 17 Van Wolferen et al reported that in patients with idiopathic pulmonary arterial hypertension (IPAH), both RV and left ventricular (LV) function as measured on CMR were improved after medical treatment, and that improvement of LV end-diastolic volume (LVEDV) was one hronic thromboembolic pulmonary hypertension (CTEPH) is characterized by the presence of organized thrombi in the pulmonary circulation and poor prognosis due to progressive right ventricular (RV) failure. 1,2 Pulmonary endarterectomy (PEA), which surgically removes organized thrombi, can cure CTEPH, 1,3-8 but distal-type CTEPH is not suitable for PEA, 8 and these inoperable CTEPH patients have poor prognosis due to progressive RV failure. As an alternative therapy, Feinstein et al originally developed balloon pulmonary angioplasty (BPA) in 2001. 9 and we and others have recently showed that BPA improves pulmonary hemodynamics, exercise capacity and prognosis in inoperable CTEPH. Background: It remains to be determined whether balloon pulmonary angioplasty (BPA) improves biventricular cardiac functions and pulmonary flow in patients with chronic thromboembolic pulmonary hypertension (CTEPH).

Several medical conditions have been reported to be involved in the development of CTEPH, including splenectomy, ventriculo-atrial shunt, inflammatory bowel disease and previous cancers. 1 These conditions increase the risk of a poor outcome in CTEPH patients. Systemic dysfunctions are also associated with pulmonary arterial hypertension (PAH) and PAH-associated death, including insulin resistance, dyslipidemia and renal hronic thromboembolic pulmonary hypertension (CTEPH) is characterized by chronic and mechanical thromboembolic obstruction of large and small pulmonary arteries, with high mortality without intervention. 1,2 Although pulmonary endarterectomy (PEA) is recommended for the treatment of CTEPH, 37% of the cases are considered inoperable. 3 Recently, we and others have demonstrated that balloon pulmonary angioplasty (BPA) markedly improves the pulmonary hemodynamics and the long-term prognosis in CTEPH patients. Background: Pulmonary arterial hypertension with systemic dysfunctions, including metabolic disorders and renal dysfunction, has a poor prognosis. However, it remains to be elucidated whether chronic thromboembolic pulmonary hypertension (CTEPH) is also associated with systemic dysfunctions, and if so, whether balloon pulmonary angioplasty (BPA) improves them.

Aims Heart failure with preserved LV ejection fraction (HFpEF) is a serious health problem worldwide, as no effective therapy is yet available. We have previously demonstrated that our low-intensity pulsed ultrasound (LIPUS) therapy is effective and safe for angina and dementia. In this study, we aimed to examine whether the LIPUS therapy also ameliorates cardiac diastolic dysfunction in mice. Methods and Results Twelve-weeks-old obese diabetic mice (db/db) and their control littermates (db/+) were treated with either the LIPUS therapy (1.875 MHz, 32 cycles, Ispta (spatial peak temporal average intensity) 117-162 mW/cm2, 0.25 W/cm2) or placebo procedure 2 times a week for 4 weeks. At 20-week-old, transthoracic echocardiography and invasive hemodynamic analysis showed that cardiac diastolic function parameters, such as e’, E/e’, end-diastolic pressure-volume relationship, Tau, and dP/dt min, were all deteriorated in placebo-treated db/db mice compared with db/+ mice, while systolic function was preserved. Importantly, these cardiac diastolic function parameters were significantly ameliorated in the LIPUS-treated db/db mice. We also measured the force (F) and intracellular Ca2+ ([Ca2+]i) in trabeculae dissected from ventricles. We found that relaxation time and [Ca2+]i decay (Tau) were prolonged during electrically stimulated twitch contractions in db/db mice, both of which were significantly ameliorated in the LIPUS-treated db/db mice, indicating that the LIPUS therapy also improves relaxation properties at tissue level. Functionally, exercise capacity was also improved in the LIPUS-treated db/db mice. Histologically, db/db mice displayed progressed cardiomyocyte hypertrophy and myocardial interstitial fibrosis, while those changes were significantly suppressed in the LIPUS-treated db/db mice. Mechanistically, Western blot showed that the eNOS-NO-cGMP-PKG pathway and Ca2+-handling molecules were up-regulated in the LIPUS-treated heart. Conclusions These results indicate that the LIPUS therapy ameliorates cardiac diastolic dysfunction in db/db mice through improvement of eNOS-NO-cGMP-PKG pathway and cardiomyocyte Ca2+-handling system, suggesting its potential usefulness for the treatment of HFpEF patients. Translational perspective Although HFpEF is a serious health problem worldwide, no effective treatment is yet available. We have previously demonstrated that our low-intensity pulsed ultrasound (LIPUS) therapy is effective and safe in animal models of angina and dementia. In this study, we examined whether our LIPUS therapy is also effective to improve cardiac diastolic dysfunction in mice. We found that the LIPUS therapy ameliorated myocardial structures and Ca2+-handling proteins, resulting in the improvement of cardiac diastolic functions and exercise tolerance in a mouse model of HFpEF. These results suggest that the LIPUS therapy is useful for the treatment of HFpEF in humans.