Depressive Status in Patients With Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: The present comparative study with healthy volunteers was conducted to investigate the depressive status and temperament in patients with chronic thromboembolic pulmonary hypertension (CTEPH).Methods and Results:The results of the temperament and personality scale test, and the Quick Inventory of Depressive Symptomatology-Self Report revealed that CTEPH patients have a significantly higher depressive status than healthy volunteers. CONCLUSIONS: It may be that CTEPH patients are more likely to have a depressive temperament in origin. It is expected that the relationship between the biological traits of CTEPH (e.g., genetics) and patients' depressive temperament will be elucidated in the future.

Alu-mediated nonallelic homologous and nonhomologous recombination in the BMPR2 gene in heritable pulmonary arterial hypertension.

PURPOSE: The purpose of this study was to undertake thorough genetic analysis of the bone morphogenetic protein type 2 receptor (BMPR2) gene in patients with pulmonary arterial hypertension. METHODS: We conducted a systematic analysis for larger gene rearrangements together with conventional mutation analysis in 152 pulmonary arterial hypertension patients including 43 patients diagnosed as having idiopathic pulmonary arterial hypertension and 10 diagnosed as having familial pulmonary arterial hypertension. RESULTS: Analysis of the BMPR2 gene revealed each of the four kinds of nonsense and frameshift mutations, one missense mutation, one splice-site mutation, and two types of exonic deletion. For cases in which exons 1-3 were deleted, the 5' and 3' break points were located in the AluY repeat sequences in the 5' side of the adjacent NOP58 gene and in the AluY repeat sequences in intron 3, suggesting an AluY-mediated nonallelic homologous recombination as the mechanism responsible for the deletion. For the case in which exon 10 was deleted, nonhomologous recombination took place between the AluSx site in intron 9 and a unique sequence in intron 10. CONCLUSION: Exonic deletions of BMPR2 account for at least part of BMPR2 mutations associated with heritable pulmonary arterial hypertension in Japan, as previously reported in other populations. One of our cases was mediated via Alu-mediated nonallelic homologous recombination and another was mediated via nonhomologous recombination.

Impact of first-line sildenafil monotreatment for pulmonary arterial hypertension.

BACKGROUND: Sildenafil has been demonstrated as effective for the treatment of pulmonary arterial hypertension (PAH). The purpose of this study was to investigate the occurrence of clinical events after sildenafil monotreatment as a first-line therapy in patients with PAH over a long-term observation period. METHODS AND RESULTS: Sildenafil was administered as a first-line drug to 46 patients with PAH (including 24 patients with idiopathic PAH) during 2003-2010. We investigated subsequent clinical events such as the addition of epoprostenol, hospitalization for right-side heart failure, and death. All the hemodynamic parameters and the 6-min walk distance improved significantly in the enrolled patients as a whole receiving sildenafil treatment; 15 (33%) of the 46 patients required the addition of epoprostenol during follow-up. Kaplan-Meier analysis demonstrated that more than 60% of the patients receiving first-line sildenafil treatment did not require the addition of epoprostenol for a 5-year period. Furthermore, the 5-year survival rate after first-line sildenafil treatment was 81%. Finally, more than 75% of the enrolled patients did not reach the composite endpoint of hospitalization for right-side heart failure and death for a 5-year period. CONCLUSIONS: This study describes the long-term outcome of patients with PAH receiving sildenafil monotreatment as a first-line therapy and suggests that it is a promising therapeutic strategy.

Platelet level as a new prognostic factor for idiopathic pulmonary arterial hypertension in the era of combination therapy.

BACKGROUND: The recent development of various effective drugs, such as epoprostenol, sildenafil, and bosentan, has improved the prognosis for patients with idiopathic pulmonary arterial hypertension (IPAH). This study sought to determine survival rates and to identify predictive prognostic factors in patients with IPAH in the current era of combination therapy with new and more effective vasodilators. METHODS AND RESULTS: In 65 consecutive IPAH patients treated from 2004 to 2009, hemodynamic parameters were significantly improved and brain natriuretic peptide was significantly decreased by combination therapy (observation period: 35±18 months). The Kaplan-Meier survival curves were determined, and 22 prognostic variables, including 9 hemodynamic variables and 6 biomarkers, were evaluated to obtain the best variables. The 1-year and 3-year survival rates were 98% and 86%, respectively. Only the platelet level was correlated with death (P<0.05), and the platelet level was significantly correlated with mean pulmonary arterial pressure (P<0.01). Patients with a lower platelet level (<20×10(4)/µl (median value)) before treatment had a higher mortality rate compared to the other patients (78% vs. 95% for 3-year survival, P<0.01). CONCLUSIONS: Combination therapy contributed to an improvement in the prognosis of IPAH patients. Platelet level is a significant prognostic predictor in this new treatment era.

Sorafenib is effective in the treatment of pulmonary veno-occlusive disease.

The present study is the first report of the effectiveness of sorafenib in the treatment of pulmonary veno-occlusive disease (PVOD). A 66-year-old woman with PVOD was started on sorafenib. After 3 months of treatment with a maximum dosage of 400 mg/day sorafenib, there was an improvement in the patient's New York Heart Association (NYHA) functional class from IV to III. However, because of severe painful eruptions as a side effect of sorafenib, the patient stopped sorafenib and was started on imatinib instead. This treatment resulted in a worsening of the patient's NYHA class from III to IV, so sorafenib was restarted at a reduced dosage of 300 mg/day. The resumption of sorafenib was associated with clinical improvement, specifically NYHA class from IV to II and hemodynamic amelioration, and tolerable eruptions. In conclusion, sorafenib may be a potential therapeutic strategy for the treatment of PVOD.

Heart rate turbulence can predict cardiac mortality following myocardial infarction in patients with diabetes mellitus.

BACKGROUND: Previous studies have described the clinical utility of heart rate turbulence (HRT) as an autonomic predictor in risk-stratifying patients after myocardial infarction (MI). Some reports showed that diabetes mellitus (DM) affects the prognostic value of autonomic markers. We assessed the utility of HRT as a risk marker in post-MI patients with DM and without DM. METHODS: We prospectively enrolled 231 consecutive DM patients and 300 non-DM patients after acute MI. HRT was measured using an algorithm based on 24-hour Holter electrocardiograms (ECGs), assessing 2 parameters: turbulence onset (TO) and turbulence slope (TS). HRT was considered positive when both TO ≥0% and TS ≤2.5 ms/R-R interval were met. The endpoint was defined as cardiac mortality. RESULTS: Of patients with DM, 9 patients (4%) were not utilized for HRT assessment because of frequent ventricular contractions or presence of atrial fibrillation. Forty-two of 222 patients (19%) were HRT positive. During follow-up of 876 ± 424 days, 26 patients (22%) reached the endpoint. Several factors including left ventricular ejection fraction (LVEF), renal dysfunction, documentation of nonsustained ventricular tachycardia (VT), and a HRT-positive outcome had significant association with the endpoint. Multivariate analysis determined that renal dysfunction and a positive HRT outcome had significant value with a hazard ratio (HR) of 4.7 (95%CI, 1.9-11.5; P = 0.0008) and 3.5 (95%CI, 1.4-8.8; P = 0.007), respectively. In non-DM patients, only a positive HRT outcome had significant value. CONCLUSIONS: This study reveals that HRT detected by 24-hour Holter ECG can predict cardiac mortality in post-MI patients whether DM is present or not.

Effects of landiolol, an ultra-short-acting beta1-selective blocker, on electrical storm refractory to class III antiarrhythmic drugs.

BACKGROUND: Occasionally it is difficult to inhibit electrical storm (ES) with standard pharmacological treatment. In the present study the effect of landiolol, an ultra-short-acting beta(1)-selective blocker, on ES refractory to class III antiarrhythmic drugs was evaluated. METHODS AND RESULTS: The study group comprised 42 consecutive patients who developed ES for which intravenous class III antiarrhythmic drugs, such as amiodarone and nifekalant, were ineffective. Landiolol was administered intravenously with an initial dose of 2.5 microg x kg(-1) x min(-1), which was doubled if it was ineffective, up to a maximum dose of 80 microg x kg(-1) x min(-1). Landiolol inhibited ES in 33 patients (79%) at a mean dose of 7.5+/-12.2 microg x kg(-1) x min(-1). All patients in whom landiolol was ineffective died of arrhythmia. Of the 33 patients in whom landiolol was effective, 25 survived and were discharged (60% of all patients). Landiolol significantly decreased heart rate (P<0.0001), but did not affect blood pressure. Landiolol was not discontinued for adverse effects in any of the responders. Age, APACHE II score, and pH of arterial blood gas differed significantly between the responders and nonresponders. CONCLUSIONS: Landiolol is useful as a life-saving drug for class III antiarrhythmic drug-resistant ES. The main mechanism of ES refractory to class III antiarrhythmic drugs could be abnormal automaticity but not reentry.

Balloon Pulmonary Angioplasty for Chronic Thromboembolic Pulmonary Hypertension: Initial Single-Center Experience.

OBJECTIVE: To evaluate the safety and efficacy of balloon pulmonary angioplasty (BPA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) seen at a US medical center. PATIENTS AND METHODS: Patients with inoperable or residual postendarterectomy CTEPH who underwent BPA at Mayo Clinic in Rochester, Minnesota, between August 11, 2014, and May 17, 2018, were included. Invasive hemodynamic, clinical, laboratory, and echocardiographic data were collected and analyzed retrospectively. RESULTS: We identified 31 patients (26 with inoperable CTEPH and 5 with residual postendarterectomy CTEPH) who underwent 75 BPA procedures performed in a staged manner to reduce complications. The median number of sessions was 2 (interquartile range [IQR], 1-3) per patient, and the number of vessels treated per session was 3 (IQR, 2-3). Of the 31 patients, 24 (77.4%) were taking pulmonary vasodilators and 22 (71.0%) were taking riociguat. The mean pulmonary arterial pressure decreased from 40 mm Hg (IQR, 29-48 mm Hg) to 29 mm Hg (IQR, 25-37 mm Hg; P<.001); pulmonary vascular resistance decreased from 5.5 Wood units (WU) (IQR, 3.0-7.6 WU) to 3.3 WU (2.2-5.2 WU; P<.001). The follow-up 6-minute walk test was performed in 13 patients and improved from 402 m (IQR, 311-439 m) to 439 m (366-510 m; P=.001). Of the 31 patients, 19 (61.3%) had improvement in New York Heart Association functional class. The mean ± SD nadir of minute ventilation/carbon dioxide production decreased by 3.4±5.5 (P=.03), reflecting improved ventilatory efficiency. Complications included hemoptysis requiring overnight intensive care unit observation (n=1) and cardiac tamponade requiring pericardiocentesis (n=1). One patient had reperfusion injury requiring intubation, recovered, and was dismissed to home but died unexpectedly within less than 30 days of the procedure. Serious complications occurred in 3 of the 75 BPA procedures (4.0%). CONCLUSION: Our experience with BPA revealed that this procedure has acceptable risk and improves hemodynamics, functional class, and exercise tolerance in patients with inoperable or residual CTEPH.

Endovascular treatment for chronic pulmonary hypertension: a focus on angioplasty for chronic thromboembolic pulmonary hypertension.

INTRODUCTION: Percutaneous transluminal pulmonary angioplasty (PTPA) was introduced for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH) in the late 20(th) century, and first attempts in collective patients were made in 2001 with beneficial effects but a moderate amount of complications. It was refined around 2010, and has been recently established as an effective and safe treatment. AREAS COVERED: The indication was originally inoperable CTEPH with peripheral lesions, but has now widened to symptomatic or hypoxic patients. The lesion is typically a meshwork-like structure of organized thrombi and is sometimes not seen as a stenosis angiographically, necessitating other means of investigation such as measurement of distal pressure. The technique to treat lesions is the same as for coronary angioplasty except in several ways. Expert commentary: The effects of PTPA are comparable to those of surgical endarterectomy, and the complications of reperfusion pulmonary edema and vascular injury are now controlled by several strategies and based on experience.

Usefulness of circulating amino acid profile and Fischer ratio to predict severity of pulmonary hypertension.

Plasma amino acid concentrations (aminogram) show distinct patterns under various pathologic conditions. However, the plasma aminogram pattern in patients with pulmonary hypertension (PH) has not been elucidated. We sought to examine whether an aminogram could be predictive of clinical severity in patients with PH. We attained fasting plasma aminograms for 140 patients with PH and then compared the patient plasma amino acid levels with those of age- and gender-matched healthy control subjects. Aminograms revealed that the plasma concentrations of many amino acids were significantly different between patients with PH and healthy control subjects. We focused on the Fischer ratio (branched-chain amino acids/aromatic amino acids) as an integrated parameter. In all enrolled patients, Fischer ratio was negatively correlated with New York Heart Association functional class (ρ = -0.37, p <0.001), plasma B-type natriuretic peptide (ρ = -0.35, p <0.001), and pulmonary vascular resistance (ρ = -0.27, p = 0.002) and positively correlated with venous oxygen saturation (ρ = 0.27, p = 0.002) and 6-minute walk distance (ρ = 0.23, p = 0.016). Time course changes in Fischer ratio and in cardiac output were significantly correlated (ρ = 0.39, p = 0.024). The aminogram is changed in patients with PH, and in these patients, Fischer ratio decreases in proportion to the clinical severity of PH.

Additional percutaneous transluminal pulmonary angioplasty for residual or recurrent pulmonary hypertension after pulmonary endarterectomy.

BACKGROUND: Pulmonary endarterectomy (PEA) has been the most effective therapy for chronic thromboembolic pulmonary hypertension (CTEPH). However, residual or recurrent pulmonary hypertension often persists after PEA. Recently, catheter-based angioplasty, called percutaneous transluminal pulmonary angioplasty (PTPA) or balloon pulmonary angioplasty, has been developed as a promising strategy for CTEPH. Therefore, the usefulness of PTPA for residual or recurrent pulmonary hypertension after PEA was investigated. METHODS: Thirty-nine patients underwent PEA from January 2000, and a total of 423 consecutive PTPA sessions in 110 patients were performed from January 2009 to May 2014. Of them, 9 patients (23.0% of 39 patients undergoing PEA and 8.2% of 110 patients undergoing PTPA) had undergone previous PEA and additional PTPA. RESULTS: In these 9 patients, pulmonary vascular resistance (PVR) was 15.6 (7.8-18.9) wood units at baseline, and significantly improved after PEA [5.6 (3.5-6.5) wood units] (p<0.05). However, PVR gradually deteriorated before PTPA [8.1 (6.1-12.3) wood units] compared to after PEA, suggesting that these 9 patients had residual or recurrent pulmonary hypertension after PEA. PTPA was performed at 4.1 (2.7-7.9) years after PEA. Follow-up catheterization at 1.9 (1.3-3.3) years after PTPA revealed significant improvement of PVR [4.2 (2.8-4.8) wood units] (p<0.05). CONCLUSIONS: A hybrid approach combining PEA and additional PTPA may be reasonable for patients with both proximal and very distal lesions not easily approachable by PEA. PTPA could be a promising alternative therapeutic strategy for residual or recurrent pulmonary hypertension after PEA.

Safety and efficacy of percutaneous transluminal pulmonary angioplasty in elderly patients.

BACKGROUND: Percutaneous transluminal pulmonary angioplasty (PTPA) is a recently developed catheter-based therapy for chronic thromboembolic pulmonary hypertension (CTEPH). The aim of the present study was to investigate the safety and efficacy of PTPA in elderly patients with CTEPH. METHODS: In all, 257 PTPA sessions in 70 patients (median age 63 years) were analyzed. Patients were divided into two groups according to age: (i) a younger group (<65 years; n=39); and (ii) an elderly group (≥65 years; n=31). RESULTS: Hemodynamic improvements were comparable between the younger and elderly groups (63.1% vs. 68.2% decrease in pulmonary vascular resistance, respectively; P>0.05). The median length of stay in the intensive care unit after each session (1.0 vs. 1.0 days) and in hospital per session (9.2 vs. 9.4 days) was similar between the two groups (P>0.05 for all). The prevalence of reperfusion pulmonary edema (23.4% vs. 26.3% across all sessions) and other complications, such as contrast dye-induced nephropathy (0% vs. 2.0%), infection (0% vs. 0%), and neurological complications (0% vs. 1.0%), was comparable in the younger vs. elderly groups (P>0.05 for all). One-year all-cause mortality was similar in the younger and elderly groups (0% vs. 3.2%, respectively; P>0.05). CONCLUSIONS: PTPA can be performed safely and effectively, even in elderly patients, and could be considered as an alternative therapeutic strategy for elderly patients who are too fragile for pulmonary endarterectomy (PEA) or who are treated in institutions without highly experienced PEA surgeons.

Pressure-wire-guided percutaneous transluminal pulmonary angioplasty: a breakthrough in catheter-interventional therapy for chronic thromboembolic pulmonary hypertension.

OBJECTIVES: This study sought to prove the safety and effectiveness of pressure-wire-guided percutaneous transluminal pulmonary angioplasty (PTPA). BACKGROUND: PTPA has been demonstrated to be effective for treatment of chronic thromboembolic pulmonary hypertension. However, a major and occasionally fatal complication after PTPA is reperfusion pulmonary edema. To avoid this, we developed the PEPSI (Pulmonary Edema Predictive Scoring Index). The pressure wire has been used to detect insufficiency of flow in a vessel. METHODS: We included 350 consecutive PTPA sessions in 103 patients with chronic thromboembolic pulmonary hypertension from January 1, 2009 to December 31, 2013. During these 5 years, 140 PTPA sessions were performed without guidance, 65 with guidance of PEPSI alone, and 145 with both PEPSI and pressure-wire guidance. Each PTPA session was finished after achieving PEPSI scores of <35.4 with PEPSI guidance and each target lesion achieving distal mean pulmonary arterial pressure <35 mm Hg with pressure-wire guidance. RESULTS: The occurrence of clinically critical reperfusion pulmonary edema and vessel injuries were lowest in the group using the guidance of both pressure wire and PEPSI (0% and 6.9%, respectively). Furthermore, the group guided by pressure wire and PEPSI accomplished the same hemodynamic improvements with fewer numbers of target lesions treated and sessions performed. CONCLUSIONS: The combined approach using pressure wire and PEPSI produced more efficient clinical results and greatly reduced reperfusion pulmonary edema and vessel complications. This is further evidence that PTPA is an alternative strategy for treating chronic thromboembolic pulmonary hypertension.

Pulmonary edema predictive scoring index (PEPSI), a new index to predict risk of reperfusion pulmonary edema and improvement of hemodynamics in percutaneous transluminal pulmonary angioplasty.

OBJECTIVES: This study sought to identify useful predictors for hemodynamic improvement and risk of reperfusion pulmonary edema (RPE), a major complication of this procedure. BACKGROUND: Percutaneous transluminal pulmonary angioplasty (PTPA) has been reported to be effective for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH). PTPA has not been widespread because RPE has not been well predicted. METHODS: We included 140 consecutive procedures in 54 patients with CTEPH. The flow appearance of the target vessels was graded into 4 groups (Pulmonary Flow Grade), and we proposed PEPSI (Pulmonary Edema Predictive Scoring Index) = (sum total change of Pulmonary Flow Grade scores) × (baseline pulmonary vascular resistance). Correlations between occurrence of RPE and 11 variables, including hemodynamic parameters, number of target vessels, and PEPSI, were analyzed. RESULTS: Hemodynamic parameters significantly improved after median observation period of 6.4 months, and the sum total changes in Pulmonary Flow Grade scores were significantly correlated with the improvement in hemodynamics. Multivariate analysis revealed that PEPSI was the strongest factor correlated with the occurrence of RPE (p < 0.0001). Receiver-operating characteristic curve analysis demonstrated PEPSI to be a useful marker of the risk of RPE (cutoff value 35.4, negative predictive value 92.3%). CONCLUSIONS: Pulmonary Flow Grade score is useful in determining therapeutic efficacy, and PEPSI is highly supportive to reduce the risk of RPE after PTPA. Using these 2 indexes, PTPA could become a safe and common therapeutic strategy for CTEPH.

Left ventricular dysfunction due to diffuse multiple vessel coronary artery spasm can be concealed in dilated cardiomyopathy.

AIMS: Many patients with idiopathic dilated cardiomyopathy (DCM) have been diagnosed on the basis of the exclusion of significant coronary stenosis and the presence of left ventricular (LV) dysfunction. In the present study, we investigated the possibility that coronary multispasm is one of the mechanisms leading to diffuse idiopathic DCM-like LV dysfunction. METHODS AND RESULTS: Forty-two patients with severely depressed LV function but without significant coronary stenosis were enrolled (baseline LV ejection fraction, 33 ± 11%). An acetylcholine (ACh) provocation test was performed at the time of coronary angiography. In patients with a positive ACh provocation test (n = 20), coronary angiography revealed multivessel diffuse coronary spasm with marked electrocardiogram changes. In patients with a negative ACh provocation test (n = 22), significant findings compatible with idiopathic DCM were more frequently observed on magnetic resonance imaging (MRI) or in LV biopsies compared with the ACh-positive group (MRI, 73% vs. 12%; and LV biopsy, 71% vs. 0%, respectively; P < 0.01). In the ACh-positive group, LV function significantly improved after the administration of calcium channel blockers (LV ejection fraction, 34 ± 12% vs. 54 ± 10%; and brain natriuretic peptide, 803 ± 482 pg/mL vs. 69 ± 84 pg/mL, at baseline and 1 year, respectively; P < 0.01). CONCLUSIONS: Our results raise the possibility that patients with LV dysfunction due to repeated coronary multispasm are being diagnosed as idiopathic DCM, and that calcium channel blockers may prove to be a promising therapeutic strategy in those patients.