Association between home-based exercise using a pedometer and clinical prognosis after endovascular treatment in patients with peripheral artery disease.

BACKGROUND: Exercise therapy following endovascular treatment (EVT) is important for patients with peripheral artery disease (PAD); however, continuous exercise therapy is difficult to be performed in clinical practice. This study aimed to investigate the association between the implementation of home-based exercise using pedometers after EVT and 1-year clinical outcomes. METHODS: This multicenter observational prospective cohort registry included patients with PAD complaining of intermittent claudication who underwent EVT for aortoiliac and/or femoropopliteal artery lesions between January 2016 and March 2019. Patients were instructed to perform home-based exercises using a specific pedometer after EVT. The study population was divided into good and poor recording groups according to the frequency of the pedometer measurements. The good recording group was defined as those who completed ≥50 % of the prescribed daily pedometer recording during the follow-up period. The poor recording group was defined as those with an inability to use a pedometer and/or who completed <50 % of the prescribed daily pedometer recordings. The primary outcome was 1-year major adverse events (MAE), defined as a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, target vessel revascularization, and major amputation of the target limb. RESULTS: The mean age was 74.4 years; 78 % were male. A total of 623 lesions were analyzed (58.7 % aortoiliac, 41.3 % femoropopliteal). At 1 year, a lower cumulative incidence of MAE was observed in the good recording group compared to that in the poor recording group [10/233 (4.3 %) vs. 35/267 (13.7 %) patients, respectively; p < 0.001]. Multivariate Cox regression analysis showed that patients in the good recording group had a lower hazard ratio for 1-year MAE (0.33; 95 % confidence interval, 0.16-0.68; p = 0.004) than that in the poor recording group. CONCLUSIONS: Good self-recording of pedometer measurements was associated with favorable prognosis in patients with PAD following EVT.

Ultrasonography is convenient and useful for assessment and follow-up of Takayasu's arteritis.

A 20-year-old woman first came to our hospital complaining of high fever and pain affecting the whole body. Takayasu's arteritis (TA) was diagnosed. Following full-body examination, many vessels between the bilateral neck and iliac arteries were found to be impaired. Ultrasonography (US) showed the characteristic wall thickening of TA in the left common carotid artery. After starting prednisolone treatment (40 mg/day), symptoms improved quickly and vessel walls gradually became thinner. However, chest pain recurred when prednisolone was tapered to 20 mg/day. Blood tests showed no signs of recurring inflammation, and US revealed worsened wall thickening only in the left carotid artery. We therefore diagnosed local recurrence of activation of TA. Assessing local recurrence of TA with a blood test is difficult, particularly after prescribing steroids. In this case, US identified the local changes attributable to TA before any other diagnostic modality. US can be useful in assessing inflammation and offers a good strategic tool for initial diagnosis of TA.

Double congenital fistulae with aneurysm diagnosed by combining imaging modalities.

Congenital coronary pulmonary artery fistula (CAF) is rare, and systemic-to-pulmonary artery fistula (SPAF) is even more so. Furthermore, congenital coronary pulmonary fistula associated with congenital SPAF is extremely rare. As far as we know, CAF and SPAF connected with an aneurysm have not been described very often. We described an 83-year-old woman with an aneurysm originating from a CAF connected to an aortopulmonary artery fistula. Chest radiography revealed a shadow at the left edge of the heart line. Multi-detector-row computed tomography (MDCT) with contrast enhancement and coronary cine angiography revealed that the shadow was an aneurysm connected to a tortuous fistula at the left anterior descending coronary artery. The aneurysm was formed by congenital coronary pulmonary and aortopulmonary artery fistulae. Echocardiography revealed predominantly systolic blood flow in the fistula from the left anterior descending coronary artery (LAD). Although neither MDCT, echocardiography nor coronary angiography alone could provide a comprehensive image of the anomaly, including the hemodynamics in the fistulae and their relationship with surrounding organs and tissues, their combination could provided important facts the led to a deeper understanding of this very uncommon occurrence.

Acute vasoreactivity testing with nicardipine in patients with pulmonary arterial hypertension.

Acute vasoreactivity testing for patients with pulmonary arterial hypertension (PAH) has been reported to be useful to identify patients with sustained beneficial response to oral calcium-channel blockers (CCBs), but there is a risk of exacerbation during the testing with oral CCBs. Therefore, we developed a testing method utilizing intravenous nicardipine, a short-acting CCB, and examined the safety and usefulness of acute vasoreactivity testing with nicardipine in PAH patients. Acute vasoreactivity testing with nicardipine was performed in 65 PAH patients. Nicardipine was administered by short-time continuous infusion (1 µg·kg⁻¹·min⁻¹ for 5 min and 2 µg·kg⁻¹·min⁻¹ for 5 min) followed by bolus injection (5 µg/kg). Hemodynamic responses were continuously measured using a right heart catheter. Acute responders were defined as patients who showed a decrease in mean pulmonary artery pressure of at least 10 mmHg to an absolute level below 40 mmHg with preserved or increased cardiac output. Two acute responders and sixty-three non-acute responders were identified. There was no hemodynamic instability requiring additional inotropic agents or death during the testing. Acute responders had good responses to long-term oral CCBs. The acute vasoreactivity testing with nicardipine might be safe and useful for identifying CCB responders in PAH patients.

Altered nano/micro-order elasticity of pulmonary artery smooth muscle cells of patients with idiopathic pulmonary arterial hypertension.

BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is a disease characterized by progressively increased resistance of pulmonary arteries. In this study, we evaluated the mechanical property of single pulmonary artery smooth muscles cells (PASMC) from patients with IPAH and tested whether the PASMC showed abnormal response to a vasodilator by use of an atomic force microscope (AFM). METHODS: PASMC were isolated and cultured from explanted lungs of 7 patients with IPAH (IPAH-PASMC). Normal vascular specimens from 3 patients with bronchogenic carcinoma were used as normal controls (normal PASMC). The nano/micro-order elasticity of five to ten living PASMC in each sample was measured by parabolic force curves of cantilever deflection/indentation obtained by using an AFM. The elasticity measurements were performed under control conditions and under condition of nitric oxide (NO) treatment (190 and 380 nmol/L). RESULTS: There was no significant difference between nano/micro-order elasticity of normal PASMC and that of IPAH-PASMC under the control conditions. In normal PASMC, NO (190 and 380 nmol/L) significantly reduced (i.e., softened) the nano/micro-order elasticity. However, NO did not reduce elasticity in IPAH-PASMC, indicating higher vasodilator-resistive nano/micro-order rigidity in IPAH-PASMC. CONCLUSION: Nano/micro-order elasticity change in PASMC in response to vasodilation induced by NO is reduced in patients with IPAH.

Inhibitory effects of simvastatin on platelet-derived growth factor signaling in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension.

Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disease characterized by inappropriate increase of pulmonary artery smooth muscle cells (PASMCs) leading to occlusion of pulmonary arterioles. Inhibition of platelet-derived growth factor (PDGF) signaling is starting to garner attention as a targeted therapy for IPAH. We assessed the inhibitory effects of simvastatin, a 3-hydroxy-3-methylglutanyl coenzyme A reductase inhibitor, on PDGF-induced proliferation and migration of PASMCs obtained from 6 patients with IPAH who underwent lung transplantation. PDGF stimulation caused a significantly higher growth rate of PASMCs from patients with IPAH than that of normal control PASMCs as assessed by (3)H-thymidine incorporation. Simvastatin (0.1 micromol/L) significantly inhibited PDGF-induced cell proliferation of PASMCs from patients with IPAH but did not inhibit proliferation of normal control cells at the same concentration. Western blot analysis revealed that simvastatin significantly increased the expression of cell cycle inhibitor p27. PDGF significantly increased the migration distance of IPAH-PASMCs compared with that of normal PASMCs, and simvastatin (1 micromol/L) significantly inhibited PDGF-induced migration. Immunofluorescence staining revealed that simvastatin (1 micromol/L) inhibited translocation of Rho A from the cytoplasm to membrane and disorganized actin fibers in PASMCs from patients with IPAH. In conclusion, simvastatin had inhibitory effects on inappropriate PDGF signaling in PASMCs from patients with IPAH.

Living-donor lobar lung transplantation for pulmonary arterial hypertension after failure of epoprostenol therapy.

OBJECTIVES: The aim of this study was to evaluate the long-term effects of living-donor lobar lung transplantation (LDLLT) for critically ill patients with pulmonary arterial hypertension (PAH) who failed in epoprostenol treatment. BACKGROUND: Although continuous epoprostenol infusion has markedly improved survival in patients with PAH, some patients do not benefit from this therapy. METHODS: From July 1998 to December 2003, 28 consecutive PAH patients who were treated with epoprostenol and accepted as candidates for lung transplantation were enrolled. All data were prospectively collected. As of July 2006, LDLLT was performed in 11 of those patients whose condition was deteriorating. Cadaveric lung transplantation (CLT) was performed in 2 patients. Medical treatment was continued in 15 patients. RESULTS: There was no mortality in patients receiving LDLLT during a follow-up period of 11 to 66 months (average 48 months), and all patients returned to World Health Organization functional class I. Mean pulmonary artery pressure decreased from 62 +/- 4 mm Hg to 15 +/- 2 mm Hg (p < 0.001) at discharge and remained normal at 3 years. One CLT patient died of primary graft failure. Among medically treated patients, 6 patients died of disease progression. The survival rate was 100% at 5 years for patients receiving LDLLT, and 80% at 1 year, 67% at 3 years, and 53% at 5 years for patients medically treated (p = 0.028). All living donors have returned to their previous lifestyles. CONCLUSIONS: These follow-up data support the option of LDLLT in patients with PAH who would die soon otherwise.

Continuous positive airway pressure ameliorated severe pulmonary hypertension associated with obstructive sleep apnea.

A 52-year-old obese woman was admitted to our institution for evaluation of dyspnea and pulmonary hypertension (PH). Polysomnography revealed severe obstructive sleep apnea (OSA) with an apnea hypopnea index of 99.8. Treatment with nocturnal continuous positive airway pressure (CPAP) resulted in correction of daytime hypoxemia, hypercapnia, and near-normalization of pulmonary artery pressure. To our knowledge, this is the most severe case of OSA-associated PH (approximately70 mmHg) reported to date, and it was successfully treated with nocturnal CPAP. This case demonstrates that OSA should be considered and polysomnography performed in all patients with PH, irrespective of severity, and that nocturnal CPAP has therapeutic effects on both OSA and daytime PH.

Carvedilol inhibits proliferation of cultured pulmonary artery smooth muscle cells of patients with idiopathic pulmonary arterial hypertension.

Idiopathic pulmonary arterial hypertension (IPAH) is associated with proliferation of smooth muscle cells (SMCs) in small pulmonary arteries. Inhibition of proliferation of pulmonary artery smooth muscle cells (PASMCs) may be an effective treatment of patients with idiopathic pulmonary arterial hypertension. Recent studies have shown that carvedilol, an alpha- and beta-blocker with antioxidant and calcium channel blocking properties, inhibits the proliferation of cultured normal human pulmonary artery smooth muscle cells. In this study, we tested the hypothesis that carvedilol has antiproliferative effects on pulmonary artery smooth muscle cells of patients with idiopathic pulmonary arterial hypertension. Pulmonary artery smooth muscle cells from six idiopathic pulmonary arterial hypertension patients who had undergone lung transplantation were cultured. To determine cell proliferation, H-thymidine incorporation was measured. Platelet-derived growth factor-induced proliferation of IPAH-PASMCs was significantly greater than that of normal control pulmonary artery smooth muscle cells. Carvedilol (0.1 microM to 10 microM) inhibited the proliferation of idiopathic pulmonary arterial hypertension-pulmonary artery smooth muscle cells in a concentration-dependent manner. Prazosin (an alpha-blocker) and N-acetyl L cysteine (an antioxidant agent) (0.1 microM to 10 microM) did not inhibit their proliferation, but the high concentration of propranolol (a beta-blocker) and nifedipine (a calcium channel blocker) (10 microM) inhibited the proliferation. The combination of propranolol and nifedipine inhibited the proliferation but only at a high concentration (10 microM) combination. Cell cycle analysis revealed that carvedilol (10 microM) significantly decreased the number of cells in S and G2/M phases. These results indicate that carvedilol inhibits the exaggerated proliferation of pulmonary artery smooth muscle cells of patients with idiopathic pulmonary arterial hypertension partially via its beta-blocking [corrected] and calcium channel blocking effects in vitro.

Prednisolone inhibits proliferation of cultured pulmonary artery smooth muscle cells of patients with idiopathic pulmonary arterial hypertension.

BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is associated with proliferation of smooth muscle cells (SMCs) in small pulmonary arteries. There is no therapy that specifically inhibits SMC proliferation. Recent studies reported that prednisolone (PSL) inhibits the postangioplasty proliferation of SMCs in atherosclerotic arteries. In this study, we tested the hypothesis that PSL has antiproliferative effects on pulmonary artery SMCs of patients with IPAH. METHODS AND RESULTS: Pulmonary artery SMCs were harvested from the pulmonary arteries of 6 patients with IPAH who underwent lung transplantation. Control SMCs were obtained from 5 patients with bronchogenic carcinoma who underwent lung lobectomy. After incubation in the presence of platelet-derived growth factor (PDGF), PSL was added at different concentrations and cell proliferation was assessed by 3H-thymidine incorporation. PSL (2x10(-4) and 2x10(-3) mol/L) significantly inhibited PDGF-stimulated proliferation (P<0.05) of SMCs from patients with IPAH but did not affect cell viability of SMCs, as confirmed by trypan blue staining. In cell cycle analysis using a microscope-based multiparameter laser scanning cytometer, PSL inhibited the progression of SMCs from G(0)/G1 to the S phase. This inhibition was associated with increased p27 expression level. PSL (2x10(-4) mol/L) also inhibited PDGF-induced SMC migration. CONCLUSIONS: Our results indicate that PSL has an antiproliferative effect on cultured SMCs of pulmonary arteries from patients with IPAH and suggest that PSL may be potentially useful therapeutically in patients with IPAH.

Risk of alveolar hemorrhage in patients with primary pulmonary hypertension--anticoagulation and epoprostenol therapy.

BACKGROUND: Anticoagulation therapy and continuous intravenous infusion of epoprostenol are the standard treatment for primary pulmonary hypertension (PPH). Because epoprostenol has an antiplatelet effect, concomitant use of an anticoagulant could increase the likelihood of hemorrhagic complications. METHODS AND RESULTS: In the present study, 31 consecutive patients with PPH (10 men, 21 women, mean +/- SD age, 28.5+/-10.1 years) treated with anticoagulation and epoprostenol between April 1999 and December 2003 were retrospectively evaluated. Clinical and hematological data at the time of the bleeding episode were retrieved from the medical records. Nine patients (22.6%) experienced 11 bleeding episodes: 9 episodes (81.8%) were alveolar hemorrhage and 2 patients were in severe respiratory distress. The mean dose of epoprostenol at the time of the first bleeding episode was 89.0 +/-40.5 ng.kg(-1).min(-1) (range, 28.1-164.0). More of the patients who did not have a bleeding episode remain alive than did patients with bleeding episodes (59% vs 33%) nor did they require lung transplantation. CONCLUSIONS: A considerable number of patients with PPH who received combined anticoagulant and high-dose epoprostenol therapy developed alveolar hemorrhage, which can be fatal.

Significance of the level of monocyte chemoattractant protein-1 in human atherosclerosis.

BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1), a potent chemoattractant for monocytes, plays an important role in the earliest events of atherogenesis. However, direct evidence of the effects of MCP-1 on atherosclerosis in chronic hemodialysis (HD) patients has not been reported. METHODS AND RESULTS: The serum MCP-1 concentrations and the intimal - medial thickness (IMT) in the carotid arteries were measured in 42 non-diabetic chronic HD patients and 20 age-matched controls. The expression of MCP-1 was examined immunohistochemically in radial arterial tissues obtained from the HD patients. IMT and the serum concentration of MCP-1 in the HD patients were both significantly greater than in controls. Multiple regression analysis revealed that the serum concentration of MCP-1 was an independent factor influencing IMT. Tissue immunostaining showed that MCP-1 is expressed in both endothelial and smooth muscle cells and that its level of expression correlates with the serum concentration of MCP-1. CONCLUSIONS: An increase in MCP-1 may be an important factor in the progression of atherosclerosis in non-diabetic HD patients.

Characterization of the bone morphogenetic protein (BMP) system in human pulmonary arterial smooth muscle cells isolated from a sporadic case of primary pulmonary hypertension: roles of BMP type IB receptor (activin receptor-like kinase-6) in the mitotic action.

The functional involvement of bone morphogenetic protein (BMP) system in primary pulmonary hypertension (PPH) remains unclear. Here we demonstrate a crucial role of the BMP type IB receptor, activin receptor-like kinase (ALK)-6 for pulmonary arterial smooth muscle cell (pphPASMC) mitosis isolated from a sporadic PPH patient bearing no mutations in BMPR2 gene. A striking increase in the levels of ALK-6 mRNA was revealed in pphPASMC compared with control PASMCs, in which ALK-6 transcripts were hardly detectable. BMP-2 and -7 stimulated the mitosis of pphPASMCs, which was opposite to their suppressive effects on the mitosis of the control PASMCs. BMP-4 and -6 and activin inhibited pphPASMC mitosis, whereas these did not affect control PASMCs. The presence of BMP signaling machinery in pphPASMCs was elucidated based on the analysis on Id-1 transcription and Smad-reporter genes. Overexpression of a dominant-negative ALK-6 construct revealed that ALK-6 plays a key role in the mitosis as well as intracellular BMP signaling of pphPASMCs. Gene silencing of ALK-6 using small interfering RNA also reduced DNA synthesis as well as Id-1 transcription in pphPASMCs regardless of BMP-2 stimulation. Although Id-1 response was not stimulated by BMP-2 in control PASMCs, the gene delivery of wild-type ALK-6 caused significant increase in the Id-1 transcripts in response to BMP-2. Additionally, inhibitors of ERK and p38 MAPK pathways suppressed pphPASMC mitosis induced by BMP-2, implying that the mitotic action is in part MAPK dependent. Thus, the BMP system is strongly involved in pphPASMC mitosis through ALK-6, which possibly leads to activation of Smad and MAPK, resulting in the progression of vascular remodeling of pulmonary arteries in PPH.

Atrial fibrillation and atrial vulnerability in patients with Brugada syndrome.

OBJECTIVES: We sought to study atrial vulnerability in patients with Brugada syndrome. BACKGROUND: Atrial fibrillation (AF) often occurs in patients with Brugada syndrome, but atrial vulnerability in Brugada syndrome has not been evaluated. METHODS: The patient group consisted of 18 patients with Brugada syndrome. The control group consisted of 12 age- and gender-matched subjects who had neither organic heart disease nor AF episodes. The incidence and clinical characteristics of AF were evaluated in all 18 patients with Brugada syndrome, and an electrophysiologic study was performed in all 12 control subjects and in 14 of the 18 patients with Brugada syndrome. The atrial effective refractory period of the right atrium (RA-ERP), intra-atrial conduction time (conduction time from the stimulus at the right atrium to atrial deflection at the distal portion of the coronary sinus), duration of local atrial potential, and repetitive atrial firing (occurrence of two or more premature atrial complexes after atrial stimulation) were studied. RESULTS: Spontaneous AF occurred in 7 of the 18 patients with Brugada syndrome but in none of the control subjects. The RA-ERP was not different between the two groups. The intra-atrial conduction time was increased in the Brugada syndrome group versus the control group (168.4 +/- 17.5 vs. 131.8 +/- 13.0 ms, p < 0.001). The duration of atrial potential at the RA-ERP was prolonged in the Brugada syndrome group versus the control group (80.3 +/- 18.0 vs. 59.3 +/- 9.2 ms, p < 0.001). Repetitive atrial firing was induced in nine patients with Brugada syndrome and in six control subjects. Atrial fibrillation was induced in eight patients with Brugada syndrome but in none of the control subjects. In patients with Brugada syndrome without spontaneous AF, the intra-atrial conduction time and duration of atrial potential were also increased. CONCLUSIONS: Atrial vulnerability is increased in patients with Brugada syndrome. Abnormal atrial conduction may be an electrophysiologic basis for induction of AF in patients with Brugada syndrome.

Recovery of cardiac function after living-donor lung transplantation in a patient with primary pulmonary hypertension.

Legislation for brain death and organ transplantation was passed in Japan in 1997, but there is still a great shortage of brain-death donors. Primary pulmonary hypertension (PPH) is a progressive disease that is usually followed by death within 5 years of diagnosis. Continuous infusion of prostacyclin is effective, but some patients will ultimately require heart-lung or lung transplantation. The first case of bilateral living-donor lobar lung transplantation (LDLLT) for PPH in Japan is reported. The recipient was a 19-year-old woman who was diagnosed as PPH at the age of 14 years and began intravenous prostacyclin therapy. Initially her symptoms improved, but she returned to New York Heart Association class IV in 2000. In January 2001, she underwent bilateral LDLLT. Postoperative echocardiography showed that the right ventricular diameter had decreased and septal wall motion had normalized, resulting in a round-shaped left ventricle. Right heart catheterization demonstrated that cardiac output and pulmonary arterial pressure had normalized. The right ventricular ejection fraction improved from 15% to 77%. The patient was discharged from hospital after 60 days postoperatively. LDLLT will become one of the options in Japan for end-stage PPH.