The role of balloon pulmonary angioplasty and pulmonary endarterectomy: Is chronic thromboembolic pulmonary hypertension still a life-threatening disease?

BACKGROUND: The management of non-operable chronic thromboembolic pulmonary hypertension (CTEPH) has evolved with the availability of balloon pulmonary angioplasty (BPA) and pulmonary vasodilators. We launched the BPA program in 2011. The aim was to analyze the survival and treatment efficacy of our CTEPH treatment program in the modern management era. METHODS AND RESULTS: We retrospectively reviewed data from 143 consecutive CTEPH patients diagnosed from January 2011 (i.e. after the availability of BPA) to December 2019. Of forty-one patients who underwent pulmonary endarterectomy (PEA), 25 underwent additional BPA (Combination group) and the others were treated with only PEA (PEA group). Ninety patients underwent BPA (BPA group). The remaining 12 patients did not undergo any interventional treatments. The 1- and 5-year survival rates of operated patients (n = 41) were 97.4% and 90.0%, compared to 96.9% and 86.9% in not-operated patients (n = 102), respectively (p = 0.579). There was no mortality in the Combination group. Mean pulmonary artery pressure after treatments in the PEA only, Combination, and BPA only groups was 20.5 ± 6.7, 17.9 ± 4.9, and 20.7 ± 4.6 mmHg, respectively (p = 0.067, one-way ANOVA). Percent decrease of pulmonary vascular resistance in each treatment groups was -73.7 ± 11.3%, -74.3 ± 11.8%, and - 54.9 ± 22.5%, respectively (p < 0.01, one-way ANOVA). CONCLUSION: There was no significant difference in long-term survival between operated and not-operated CTEPH. Moreover, the Combination approach might have the potential to introduce notable improvements in the prognosis of CTEPH. BPA and PEA appear to be mutually complementary therapies in the modern management era.

Green tea cultivar 'Benifuuki' potentiates split vaccine-induced immunoglobulin A production.

Influenza is a widespread disease caused by infection with the influenza virus. Vaccination is considered to be the main countermeasure against influenza. A split vaccine is widely used to avoid severe adverse events, and it induces strong humoral immunity. However, the split vaccine alone cannot elicit mucosal immunity, including IgA production, and its preventative effects are limited. Here, we show that the green tea cultivar 'Benifuuki' extract enhanced the effect of a split vaccine on mucosal immunity. The frequency of IgA+ cells was increased in lung and Peyer's patch that received Benifuuki diet. Secretion of hemagglutinin-specific mucosal IgA, which is closely linked to the prevention of viral infection, was significantly increased in the bronchoalveolar lavage fluid of split vaccine-immunized BALB/c mice that were administered green tea Benifuuki extract. Our findings suggest that Benifuuki intake enhanced the effects of the split vaccine on mucosal immunity.

Orally administered dipeptidyl peptidase-4 inhibitor (alogliptin) prevents abdominal aortic aneurysm formation through an antioxidant effect in rats.

OBJECTIVE: Dipeptidyl peptidase-4 (DPP-4) inhibitor, a novel antidiabetic drug, has a cardioprotective effect on ischemia-reperfusion injury through an antioxidant effect. However, the effect of DPP-4 inhibitor on aneurysm formation has not been investigated. We aimed to test the hypothesis that the DPP-4 inhibitor, alogliptin, attenuates vascular oxidative stress and thus inhibits abdominal aortic aneurysm (AAA) formation. METHODS: AAAs were created with intraluminal elastase and extraluminal calcium chloride in 36 male rats. Rats were divided into three groups: a low dose of alogliptin group (group LD; 1 mg/kg/d), a high-dose group (group HD; 3 mg/kg/d), and a control group (group C, water). Alogliptin was administered by gastric gavage once daily beginning 3 days before surgery. On day 7 after aneurysm preparation, reactive oxygen species (ROS) expression was semiquantified by dihydroethidium staining, and the oxidation product of DNA produced by ROS, 8-hydroxydeoxyguanosine (8-OHdG), was measured by immunohistochemical staining. Blood glucose concentrations were measured. Hematoxylin and eosin and elastica Van Gieson stainings were performed on day 28, and the AAA dilatation ratio was calculated. RESULTS: On day 7 (six in each group), dihydroethidium staining of the aneurysm wall showed a reduced level of ROS expression (4.6 ± 0.6 in group C, 2.7 ± 0.3 in group LD, and 1.7 ± 0.5 in group HD; P < .0001) and showed fewer 8-OHdG-positive cells in alogliptin-treated samples (138.1 ± 7.4 cells in group C, 102.5 ± 4.5 cells in group LD, and 66.1 ± 4.5 cells in group HD; P < .0001) The treatment significantly reduced messenger RNA expression of matrix metalloproteinases (MMPs) in aneurysm walls (relative expression: MMP-2: 2.1 ± 0.4 in group C, 1.3 ± 0.3 in group LD, and 0.9 ± 0.2 in group HD; P < .001; MMP-9: 2.0 ± 0.5 in group C, 0.3 ± 0.3 in group LD, and 0.3 ± 0.2 in group HD; P < .001). On day 28 (six in each group), the aortic wall in groups LD and HD was less dilated (dilatation ratio: 199.2% ± 11.8% in group C, 159.6% ± 2.8% in group LD, and 147.1% ± 1.9% in group HD; P < .02 group C vs HD) and had higher elastin content than in group C. The difference in blood glucose levels among the three groups was not significant. CONCLUSIONS: The DPP-4 inhibitor, alogliptin, attenuates aneurysm formation and expansion dose-dependently in a rat AAA model via an antioxidative action.

Free-radical scavenger edaravone inhibits both formation and development of abdominal aortic aneurysm in rats.

OBJECTIVE: An ideal pharmaceutical treatment for abdominal aortic aneurysm (AAA) is to prevent aneurysm formation and development (further dilatation of pre-existing aneurysm). Recent studies have reported that oxidative stress with reactive oxygen species (ROS) is crucial in aneurysm formation. We hypothesized that edaravone, a free-radical scavenger, would attenuate vascular oxidative stress and inhibit AAA formation and development. METHODS: An AAA model induced with intraluminal elastase and extraluminal calcium chloride was created in 42 rats. Thirty-six rats were divided three groups: a low-dose (group LD; 1 mg/kg/d), high-dose (group HD; 5 mg/kg/d), and control (group C, saline). Edaravone or saline was intraperitoneally injected twice daily, starting 30 minutes before aneurysm preparation. The remaining six rats (group DA) received a delayed edaravone injection (5 mg/kg/d) intraperitoneally, starting 7 days after aneurysm preparation to 28 days. AAA dilatation ratio was calculated. Pathologic examination was performed. ROS expression was semi-quantified by dihydroethidium staining and the oxidative product of DNA induced by ROS, 8-hydroxydeoxyguanosine (8-OHdG), by immunohistochemical staining. RESULTS: At day 7, ROS expression and 8-OHdG-positive cells in aneurysm walls were decreased by edaravone treatment (ROS expression: 3.0 ± 0.5 in group LD, 1.7 ± 0.3 in group HD, and 4.8 ± 0.7 in group C; 8-OHdG-positive cells: 106.2 ± 7.8 cells in group LD, 64.5 ± 7.7 cells in group HD, and 136.6 ± 7.4 cells in group C; P < .0001), compared with group C. Edaravone treatment significantly reduced messenger RNA expressions of cytokines and matrix metalloproteinases (MMPs) in aneurysm walls (MMP-2: 1.1 ± 0.5 in group LD, 0.6 ± 0.1 in group HD, and 2.3 ± 0.4 in group C; P < .001; MMP-9: 1.2 ± 0.1 in group LD, 0.2 ± 0.6 in group HD, and 2.4 ± 0.2 in group C; P < .001). At day 28, aortic walls in groups LD and HD were less dilated, with increased wall thickness and elastin content than those in group C (dilatation ratio: 204.7% ± 16.0% in group C, 156.5% ± 6.6% in group LD, 136.7% ± 2.0% in group HD; P < .0001). Delayed edaravone administration significantly prevented further aneurysm dilatation, with increased elastin content (155.2% ± 2.9% at day 7, 153.1% ± 11.6% at day 28; not significant). CONCLUSIONS: Edaravone inhibition of ROS can prevent aneurysm formation and expansion in the rat AAA model. Free-radical scavenger edaravone might be an effective pharmaceutical agent for AAA in clinical practice.

Low-dose edaravone injection into the clamped aorta prevents ischemic spinal cord injury.

Previous studies have indicated that high-dose intravenous edaravone (3-10mg/kg) protects against ischemic spinal cord injury. This study examined whether direct injection of low-dose edaravone into the clamped segment of the aorta prevents ischemic spinal cord injury. Spinal cord ischemia was induced in rabbits by aortic clamping below the renal artery and above the aortic bifurcation for 15min at normothermia. In groups A and B, 3 and 1mg/kg of edaravone, respectively, was injected into the clamped segment of the aorta immediately following aortic clamping. In group C, saline was injected. Neurological function was assessed at 8, 24, and 48hr and 7 days after reperfusion with Tarlov criteria. The spinal cord was histologically examined at 7 days with hematoxylin-eosin staining and in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. The Tarlov score remained grade 4 throughout the period in groups A and B, whereas it dropped to grade 0 or 1 at 7 days in group C, significantly higher in the former two groups. The number of intact motor neurons was significantly greater in groups A and B with less necrotic motor neurons than in group C. There was no significant difference in terms of spinal cord protection between groups A and B. There was no TUNEL-positive neuron in any group, indicating the absence of apoptosis. Low-dose intra-aortic edaravone injection prevents immediate neuronal injury by reducing neuronal cell damage in the early stage as well as delayed neuronal injury at 7 days.

Transcranial motor-evoked potentials following intra-aortic cold blood infusion facilitates detection of critical supplying artery of spinal cord.

OBJECTIVE: In order to determine whether critical intercostal artery is present in the aneurysm during descending thoracic or thoracoabdominal aortic surgery, changes of transcranial motor-evoked potentials (Tc-MEPs) were monitored following infusion of cold blood into the aorta as an adjunct 'on-site assessment'. Accuracy of this method was evaluated. METHODS: Fourteen patients were examined for Tc-MEPs changes following infusion of cold blood (4 degrees C, 300-450 ml) into the aneurysm. The intercostal arteries in the aneurysm were reconstructed when the Tc-MEPs amplitude decreased to below 50% of the baseline within 3 min after cold blood infusion. When the amplitude did not decrease, every intercostal artery in the aneurysm was ligated. RESULTS: The Tc-MEPs amplitude did not decrease in eight cases (57%), while it decreased in six cases (43%). In the former, no case presented with paraplegia despite every intercostal artery being ligated. In the latter, the amplitude recovered after reconstruction in four patients, who had no paraplegia postoperatively. In the remaining two cases, however, the amplitude did not recover: one died of multiple organ failure with postoperative assessment unfeasible; the other developed paraplegia following surgery. Except one case with operative death, both sensitivity and specificity of our criteria with cold blood infusion was 100% in this series. CONCLUSIONS: Cold blood infusion into the clamped segment of aorta accelerates Tc-MEPs changes and can possibly reduce ischemic insults of spinal cord during diagnostic process, while it accurately detects presence of critical intercostal artery in the segment. This method appears to be promising adjunct on-site assessment.

Intra-aortic injection of propofol prevents spinal cord injury during aortic surgery.

OBJECTIVE: We investigated whether propofol, a widely used anesthetic, injected into clamped aortic segments quickly attenuated transcranial spinal motor-evoked potential (MEP) amplitudes and protected against spinal cord injury during thoracoabdominal aortic surgery. METHODS: Eighteen beagle dogs were divided into three groups (n=6, each group): group 1 (20 ml of saline, intra-aortic injection), group 2 (1.5 mg/kg of propofol, intravenous injection), and group 3 (1.5 mg/kg of propofol, intra-aortic injection). Aortic cross-clamping was performed for 30 min. In each group, MEP amplitudes were recorded before, during, and after aortic cross-clamping. Tarlov score and histopathological examination were used to evaluate the protective effects of intra-aortic propofol injections. RESULTS: MEP amplitudes in group 3 attenuated to a value that was 60% of the control in just a minute after aortic cross-clamping, but maintained 40% of the control value during aortic cross-clamping. However, MEP amplitudes in groups 1 and 2 gradually attenuated and almost disappeared. Groups 1 and 2 amplitudes were lower than those in group 3, 30 min after aortic cross-clamping (p<0.001). Twenty-four hours after ischemia, the Tarlov score in group 3 was 3.5+/-0.5 and was higher than scores from groups 1 and 2, which were 0.5+/-0.5 and 1.3+/-1.2 (mean+/-SD, p<0.001, and p<0.001), respectively. Histopathologically, normal spinal cord motor neurons in group 3 were preserved to a significantly greater extent than in groups 1 and 2 (p=0.0031, and p=0.0282, respectively). There was a strong correlation between Tarlov scores at 24h and the number of normal motor neurons in the anterior horns of spinal cords (r=0.897; p<0.001). CONCLUSIONS: Intra-aortic propofol injections produce the quick suppression of MEP amplitudes and protect spinal cords from ischemia during aortic cross-clamping.