Arrhythmogenic Right Ventricular Cardiomyopathy Diagnosed during Hospitalization for Cardiac Arrest.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically mediated cardiomyopathy charac-terized by progressive myocardial loss of the right ventricle and its replacement by fibrofatty tissue, causing dyskinesia, aneurysm, and/or arrhythmia. The prevalence of ARVC is estimated to be 1 in 2,000-5,000, with the condition accounting for up to 20% of sudden cardiac deaths in individuals < 35 years old. This report describes the case of 61-year-old Japanese who was diagnosed with ARVC after cardiac arrest (CA) and successful resusci-tation. After the sudden CA, the restoration of spontaneous circulation was achieved with appropriate resusci-tation, followed by the introduction of target temperature management in the intensive care unit. He was diag-nosed with ARVC based on angiography and histology results. An ICD (implantable cardioverter-defibrillator) was implanted, and he was discharged without neurological sequelae 1 month post-CA. ARVC is an important cause of sudden CA, and successfully resuscitated patients with right ventricular dilation should undergo testing to rule out ARVC.

Coronary artery calcification scoring system based on the coronary artery calcium data and reporting system (CAC-DRS) predicts major adverse cardiovascular events or all-cause death in patients with potentially curable lung cancer without a history of cardiovascular disease.

The coronary artery calcium data and reporting system (CAC-DRS) is a novel reporting system based on CAC severity. Lung cancer patients have a high risk of cardiovascular disease (CVD), for which CAC severity may provide additional prognostic information. Using non-gated, non-contrast computed tomography (CT), we evaluated the CAC-DRS for predicting CVD and all-cause death in patients with potentially curable resected lung cancer. We retrospectively studied 309 consecutive patients without a history of CVD (mean age 67.4 ± 8.2 years, 61% male) who underwent curative surgery for non-small-cell lung cancer between May 2012 and March 2019 at the Japanese Red Cross Okayama Hospital. Time to incidence of major adverse cardiac events (MACEs) (non-fatal myocardial infarction, non-fatal stroke and cardiovascular death) and all-cause death was analyzed using Fine and Gray and Cox regression models. The CAC-DRS score was assessed using standard chest CT without electrocardiogram gating. During 52-months' median follow-up, 43 patients (13.4%) developed incident MACEs or died from any cause; the pathological cancer stages were Ia (n = 20), Ib (n = 8), IIa (n = 2), IIb (n = 2) and IIIa (n = 11). Patients had a graded increase in incidence of MACEs or all-cause death with increasing categories of CAC-DRS. The CAC-DRS score was significantly associated with incident MACEs or all-cause death after adjusting for confounding factors (hazard ratio 1.18; 95% confidence interval 1.10-1.25, p < 0.01). In conclusion, the CAC-DRS score on non-gated standard CT can predict incident MACEs and/or all-cause death in patients with potentially curable resected lung cancer. Lung cancer survivors with a greater CAC-DRS category may need more active management of cardiovascular risk factors.

Indirect Calorimetry Measurement of Energy Expenditure Related to Body Position Changes in Healthy Adults.

Early mobilization is advocated to prevent intensive care unit-acquired physical weakness, but the patient's workload and its changes in response to body position changes have not been established. We used indirect calorimetry to determine the energy expenditure (EE) in response to body position changes, and we assessed EE's correlation with respiratory parameters in healthy volunteers: 8 males and 8 females, mean age 23.4±1.3 years. The subjects started in the resting supine position followed by a 30° head-up position, a 60° head-up position, an upright sitting position, a standing position, and the resting supine position. EE was determined in real time by indirect calorimetry monitoring the subject's respiratory rate, tidal volume (VT), and minute volume (MV). The highest values were observed immediately after the subjects transitioned from standing to supine, and this was significantly higher compared to the original supine position (1,450±285 vs. 2,004±519 kcal/day, p<0.01). Moderate correlations were observed between VT and EE (r=0.609, p<0.001) and between MV and EE (r=0.576, p<0.001). Increasing VT or MV indicates an increasing patient workload during mobilization. Monitoring these parameters may contribute to safe rehabilitation. Further studies should assess EE in critically ill patients.

Diagnostic Accuracy of Three Different Protocols for 3.0T Coronary Magnetic Resonance Angiography.

The usefulness of coronary magnetic resonance angiography (cMRA) has been reported, although the difference in the diagnostic accuracy of different protocols has not been established.We compared conventional coronary angiography (CAG) and cMRA, conducted within 6 months in 24 consecutive patients between September 2012 and July 2014. Three cMRA protocols were examined, cMRA1, free-breathing wholeheart coronary angiography (WHCA) without contrast; cMRA2, free-breathing WHCA with contrast; and cMRA3, breath-hold steady-state free precession with contrast using a 3.0 T scanner. Image quality was graded on a 4-point scale: 1) nonassessable; 2) assessable, fair vessel contrast; 3) assessable, good vessel contrast; and 4) assessable, excellent vessel contrast. Significant narrowing of the coronary arteries was visually assessed.Stenosis was observed in 34 segments, with a prevalence of 10.3%. For cMRA1, cMRA2, and cMRA3, the numbers of assessable segments were 245 (74.2%), 287 (87.0%), and 164 (49.7%), respectively (P < 0.001 by the McNemar test). For assessable segments, the sensitivity, specificity, positive predictive value, and negative predictive value were 89.3%, 99.1%, 92.6%, and 98.6% for cMRA1, 90.0%, 98.1%, 84.4%, and 98.8% for cMRA2, and 76.5%, 93.9%, 59.1%, and 97.1% for cMRA3, respectively. For the assessable segments, the image quality score was better with cMRA2 than with the other two protocols.cMRA is a useful modality to rule out coronary artery disease, especially the cMRA2 protocol, which performed better than the other two protocols.

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.

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.

Effects of luseogliflozin and voglibose on high-risk lipid profiles and inflammatory markers in diabetes patients with heart failure.

Sodium-glucose cotransporter 2 inhibitors could reduce cardiovascular events in patients with heart failure irrespective of diabetes status. In this prespecified sub-analysis of randomised-controlled trial, we investigated the efficacy of luseogliflozin (2.5 mg daily), a sodium-glucose cotransporter 2 inhibitor, with that of voglibose (0.6 mg daily), an alpha-glucosidase inhibitor, on high-risk lipid profile and inflammatory markers in patients with type-2 diabetes and heart failure. Among the 157 patients studied, there were no significant differences in the mean malondialdehyde LDL or small-dense LDL cholesterol levels between the luseogliflozin and voglibose groups (percent change: 0.2% vs. - 0.6%, p = 0.93; - 1.7% vs. - 8.6%, p = 0.21) after 12 weeks in comparison to levels at the baseline. No significant difference was observed between the two groups in the adiponectin and high-sensitivity C-reactive protein levels after 12 weeks compared to the baseline levels (percent change, - 1.6% vs. - 4.0% and 22.5% vs. 10.0%; p = 0.52 and p = 0.55, respectively). In conclusion, in patients with type-2 diabetes and heart failure, compared to voglibose, luseogliflozin did not significantly improve the high-risk lipoprotein profile including malondialdehyde LDL and small-dense LDL cholesterol or the levels of inflammatory markers, including adiponectin and high-sensitivity C-reactive protein.Trial registration: Trial number: UMIN-CTR, UMIN000018395; Registered 23 July 2015; URL: https://www.umin.ac.jp/ctr/index.htm .

Effects of luseogliflozin on estimated plasma volume in patients with heart failure with preserved ejection fraction.

AIMS: Sodium glucose co-transporter 2 inhibitors have diuretic effects in both patients with glycosuria and with natriuresis. We sought to assess the effect of luseogliflozin on estimated plasma volume (ePV) in patients with type 2 diabetes and heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: This study was a post-hoc analysis of the MUSCAT-HF trial (UMIN000018395), a multicentre, prospective, open-label, randomized controlled trial that assessed the effect of 12 weeks of luseogliflozin (2.5 mg, once daily, n = 83) as compared with voglibose (0.2 mg, three times daily, n = 82) on the reduction in brain natriuretic peptide (BNP) in patients with type 2 diabetes and HFpEF. The analysis compared the change in ePV calculated by the Straus formula from baseline to Weeks 4, 12, and 24, using a mixed-effects model for repeated measures. We also estimated the association between changes in ePV and changes in other clinical parameters, including BNP levels. Luseogliflozin significantly reduced ePV as compared to voglibose at Week 4 {adjusted mean group-difference -6.43% [95% confidence interval (CI): -9.11 to -3.74]}, at Week 12 [-8.73% (95%CI: -11.40 to -6.05)], and at Week 24 [-11.02% (95%CI: -13.71 to -8.33)]. The effect of luseogliflozin on these parameters was mostly consistent across various patient clinical characteristics. The change in ePV at Week 12 was significantly associated with log-transformed BNP (r = 0.197, P = 0.015) and left atrial volume index (r = 0.283, P = 0.019). CONCLUSIONS: Luseogliflozin significantly reduced ePV in patients with type 2 diabetes and HFpEF, as compared with voglibose. The reduction of intravascular volume by luseogliflozin may provide clinical benefits to patients with type 2 diabetes and HFpEF.

Detrended fluctuation analysis can detect the impairment of heart rate regulation in patients with heart failure with preserved ejection fraction.

BACKGROUND: The impairment of short-term heart rate regulation in patients with heart failure with preserved ejection fraction (HFpEF) can cause acute hemodynamic collapse. Detrended fluctuation analysis (DFA) is a useful tool for the diagnosis of heart diseases and the prediction of mortality. In DFA, the short-term scaling exponent α is decreased in heart failure. However, its change in HFpEF patients remains unclear. METHODS: Twenty patients diagnosed with HFpEF [defined as brain natriuretic peptide (BNP) >100 pg/mL, ejection fraction (EF) ≥50%, and without significant valvular disease], 20 diagnosed with non-HFpEF (BNP > 100 pg/mL and EF < 50%), and 20 control subjects generally matched for age and gender were enrolled. Holter electrocardiography was performed, and heart rate variability was calculated. In the DFA, the scaling exponents in 1000 beats were calculated for each 15-min segment and the average of all segments was used. We compared both the short-term (<11 beats, α1) and long-term (≥11 beats, α2) scaling exponents among the three groups. RESULTS: In the HFpEF, non-HFpEF, and control groups, α1 was 0.73 ± 0.27, 0.66 ± 0.29, and 1.01 ± 0.20 (p < 0.01), and α2 was 0.95 ± 0.08, 0.88 ± 0.11, and 0.96 ± 0.07 (p < 0.01), respectively. The α1 exponent was significantly decreased in the HFpEF group (p < 0.01 vs. control) and the non-HFpEF group (p < 0.01 vs. control), while the α2 exponent was significantly decreased in the non-HFpEF group only (p < 0.05 vs. HFpEF and control). CONCLUSIONS: Short-term heart rate regulation is impaired in patients with HFpEF, while patients with non-HFpEF have both short-term and long-term impairment.

Effect of Luseogliflozin on Heart Failure With Preserved Ejection Fraction in Patients With Diabetes Mellitus.

Background Effects of sodium-glucose cotransporter 2 inhibitors on reducing hospitalization for heart failure have been reported in randomized controlled trials, but their effects on patients with heart failure with preserved ejection fraction (HFpEF) are unknown. This study aimed to evaluate the drug efficacy of luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, in patients with type 2 diabetes mellitus and HFpEF. Methods and Results We performed a multicenter, open-label, randomized, controlled trial for comparing luseogliflozin 2.5 mg once daily with voglibose 0.2 mg 3 times daily in patients with type 2 diabetes mellitus suffering from HFpEF (left ventricular ejection fraction >45% and BNP [B-type natriuretic peptide] concentrations ≥35 pg/mL) in a 1:1 randomization fashion. The primary outcome was the difference from baseline in BNP levels after 12 weeks of treatment between the 2 drugs. A total of 173 patients with diabetes mellitus and HFpEF were included. Of these, 83 patients were assigned to receive luseogliflozin and 82 to receive voglibose. There was no significant difference in the reduction in BNP concentrations after 12 weeks from baseline between the 2 groups. The ratio of the mean BNP value at week 12 to the baseline value was 0.79 in the luseogliflozin group and 0.87 in the voglibose group (percent change, -9.0% versus -1.9%; ratio of change with luseogliflozin versus voglibose, 0.93; 95% CI, 0.78-1.10; P=0.26). Conclusion In patients with type 2 diabetes mellitus and HFpEF, there is no significant difference in the degree of reduction in BNP concentrations after 12 weeks between luseogliflozin and voglibose. Registration URL: https://www.umin.ac.jp/ctr/index.htm; Unique identifier: UMIN000018395.

4-Hydroxy-2-nonenal induces calcium overload via the generation of reactive oxygen species in isolated rat cardiac myocytes.

BACKGROUND: It has been reported that that the amount of 4-hydroxy-2-nonenal (HNE), which is a major lipid peroxidation product and a cytotoxic aldehyde, is increased in the human failing myocardium. This study was designed to determine whether HNE has a pro-oxidant effect in cardiac myocytes and whether HNE causes Ca(2+) overload. METHODS AND RESULTS: Exposure to HNE for 10 minutes in the presence of ferric nitrilotriacetate induced the production of hydroxyl radical (.OH) in the rat myocardium as assessed by electron spin resonance spectroscopy, and HNE induced the generation of reactive oxygen species (ROS) in a dose-dependent manner as assessed by 2', 7'-dichlorofluorescein diacetate fluorescence. HNE increased intracellular Ca(2+) concentration ([Ca(2+)](i)) as assessed by fura-2 ratio in a dose- and time-dependent manner. After 20 minutes of HNE (400 micromol/L) exposure, hypercontracture was induced in 67% of the cells. Catalase, an antioxidative enzyme that can decompose hydrogen peroxide (H(2)O(2)), significantly attenuated the increase in [Ca(2+)](i) and completely inhibited hypercontracture. Carvedilol, a beta-blocker with potent antioxidant activity, also significantly attenuated the increase in [Ca(2+)](i) and completely inhibited hypercontracture, but propranolol had no effect on either [Ca(2+)](i) increase or hypercontracture. CONCLUSIONS: HNE induces the formation of ROS, especially H(2)O(2) and .OH, in cardiomyocytes and subsequently ROS cause intracellular Ca(2+) overload. HNE formation may play an important role as a mediator of oxidative stress in heart failure.

Correction to: Physiological insights of recent clinical diagnostic and therapeutic technologies for cardiovascular diseases.

The article Physiological insights of recent clinical diagnostic and therapeutic technologies for cardiovascular diseases, written by Kenji Shigemi, Soichiro Fuke, Dai Une, Keita Saku, Shuji Shimizu, Toru Kawada, Toshiaki Shishido, Kenji Sunagawa and Masaru Sugimachi, was originally published Online First without open access.

Physiological insights of recent clinical diagnostic and therapeutic technologies for cardiovascular diseases.

Diagnostic and therapeutic methods for cardiovascular diseases continue to be developed in the 21st century. Clinicians should consider the physiological characteristics of the cardiovascular system to ensure successful diagnosis and treatment. In this review, we focus on the roles of cardiovascular physiology in recent diagnostic and therapeutic technologies for cardiovascular diseases. In the first section, we discuss how to evaluate and utilize left ventricular arterial coupling in the clinical settings. In the second section, we review unique characteristics of pulmonary circulation in the diagnosis and treatment of pulmonary hypertension. In the third section, we discuss physiological and anatomical factors associated with graft patency after coronary artery bypass grafting. In the last section, we discuss the usefulness of mechanical ventricular unloading after acute myocardial infarction. Clinical development of diagnostic methods and therapies for cardiovascular diseases should be based on physiological insights of the cardiovascular system.

Clinical significance of platelet reactivity during prasugrel therapy in patients with acute myocardial infarction.

BACKGROUND: Although some studies have examined platelet reactivity (PR) during prasugrel treatment, little is known about PR during the early treatment period and its clinical significance in Japan. METHODS: We investigated the early and medium-term efficacy and safety of prasugrel in patients with acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PCI). Seventy-eight patients were enrolled and PR was measured (in P2Y12 reaction units; PRU) by the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA, USA). RESULTS: In 44 patients, serial measurement revealed that PR was significantly higher at 2h after administration of the 20-mg loading dose of prasugrel than on the morning of the second day at 17.6±6.6h after administration (191.6±75.5 vs. 138.5±68.9PRU). During the 8-month follow-up period, bleeding events occurred in 18 patients (23.1%) (GUSTO minor: 15 patients). Multivariate regression analysis identified oral anticoagulant use as a significant predictor of bleeding events during admission [odds ratio (OR): 4.214, 95% confidence interval (CI): 1.005-17.669, p=0.049]. Administration of prasugrel via a nasogastric tube was a significant predictor of high on-treatment platelet reactivity (HTPR) (PRU≥230) (OR: 43.100, 95% CI: 4.517-411.251, p=0.001). In addition, HTPR was a significant predictor of major adverse cardiac events (cardiovascular death, non-fatal myocardial infarction, stent thrombosis, stroke, and sustained ventricular tachycardia) during the 8-month follow-up period (OR: 4.911, 95% CI: 1.164-20.722, p=0.030). CONCLUSIONS: It is feasible to treat AMI patients with prasugrel. HTPR is a significant independent risk factor for adverse events in AMI patients receiving prasugrel after primary PCI.

Differences in clinical and angiographic outcomes with different drug-eluting stents in Japanese patients with and without diabetes mellitus.

BACKGROUND: Although percutaneous coronary intervention (PCI) in patients with diabetes mellitus (DM) is associated with worse clinical outcomes, the efficacy of drug-eluting stents (DES) in Japanese patients and differences in effectiveness between different DES types remain unknown. METHODS AND SUBJECTS: Five-hundred and sixty-two consecutive patients (183 with DM, 379 without DM) with 676 lesions were treated with sirolimus-eluting stents (SES, n=531; 160 DM group, 371 non-DM group) or paclitaxel-eluting stents (PES, n=145; 64 and 81, respectively). We assessed the initial and 8-month follow-up clinical and angiographic outcomes. RESULTS: There were no significant differences in clinical and lesion characteristics, although the pre-minimum luminal diameter was smaller in the DM group (p=0.016). The risk of major adverse cardiac events (MACE), defined as cardiac death, non-fatal myocardial infarction, congestive heart failure, or recurrent angina pectoris, was higher in the DM group compared with the non-DM group (17.4% vs 9.5%, p=0.007). Among diabetic patients, although SES reduced late loss by 0.45 mm (p<0.001) and the binary restenosis rate by 66.4% (7.4% vs 22.0%, p<0.001) compared with PES at 8 months, it did not reduce target lesion revascularization or MACE, as in the non-DM group. CONCLUSIONS: Diabetic patients have worse mid-term prognosis than non-diabetic patients undergoing PCI with DES. Although the superiority of SES in terms of late loss or restenosis may not play a clinically meaningful role in the treatment of diabetic patients, this phenomenon was independent of the presence of diabetes.

Five-year clinical outcomes after implantation of sirolimus-eluting stents in patients with and without diabetes mellitus.

Percutaneous coronary intervention in patients with diabetes mellitus (DM) is associated with worse clinical outcomes; however, the long-term efficacy of sirolimus-eluting stents (SES) in diabetic patients remains uncertain. We evaluated 5-year clinical outcomes after SES implantation in 197 consecutive patients (85 in the DM group and 112 in the non-DM group), and 246 lesions (106 and 140, respectively). The primary end point was major adverse cardiac events (MACE) defined as cardiac death, nonfatal myocardial infarction, target lesion revascularization (TLR), stent thrombosis or admission for congestive heart failure. Diabetic patient characteristics included 32 % who used insulin. The risk of congestive heart failure was significantly higher [20.0 vs. 5.4 %, odds ratio (OR) 4.417, 95 % confidence interval (CI) 1.659 to 11.759, p = 0.003] in the DM group compared with the non-DM group; however, MACE did not occur significantly more often (27.1 vs. 16.1 %, p = 0.060). Multivariate logistic regression analysis showed that diabetes was associated with congestive heart failure (OR 4.715, 95 % CI 1.743 to 12.759, p = 0.002) and multivessel disease was associated with major adverse cardiac events (OR 2.709, 95 % CI 1.053 to 6.965, p = 0.039). The cumulative rates (%) of TLR were as follows: after 1 year; 5.9 versus 5.4, 2 years; 7.1 versus 5.4, 3 years; 9.4 versus 7.1, 4 years; 9.4 versus 8.9, 5 years; 9.4 versus 8.9 (p = 0.652) in the DM group and the non-DM group, respectively. Diabetic patients had worse long-term prognosis in terms of congestive heart failure than non-diabetic patients undergoing PCI, even with SES. TLR was performed steadily for up to 5 years of follow-up following the late catch-up phenomenon both in diabetic and non-diabetic patients.

Pro-apoptotic effects of imatinib on PDGF-stimulated pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension.

BACKGROUND: Remodeling of the pulmonary artery by an inappropriate increase of pulmonary artery smooth muscle cells (PASMCs) is problematic in the treatment of idiopathic pulmonary arterial hypertension (IPAH). Effective treatment that achieves reverse remodeling is required. The aim of this study was to assess the pro-apoptotic effects of imatinib, a platelet-derived growth factor (PDGF)-receptor tyrosine kinase inhibitor, on PASMCs obtained from patients with IPAH. METHODS: PASMCs were obtained from 8 patients with IPAH undergoing lung transplantation. Cellular proliferation was assessed by (3)H-thymidine incorporation. Pro-apoptotic effects of imatinib were examined using TUNEL and caspase-3,7 assays and using transmission electron microscopy. RESULTS: Treatment with imatinib (0.1 to 10 µg/mL) significantly inhibited PDGF-BB (10 ng/mL)-induced proliferation of PASMCs from IPAH patients. Imatinib (1 µg/mL) did not induce apoptosis in quiescent IPAH-PASMCs, but it had a pro-apoptotic effect on IPAH-PASMCs stimulated with PDGF-BB. Imatinib did not induce apoptosis in normal control PASMCs with or without PDGF-BB stimulation. PDGF-BB induced phosphorylation of Akt at 15 min, and Akt phosphorylation was inhibited by imatinib in IPAH-PASMCs. Akt-I-1/2 (1 µmol/L), an Akt inhibitor, in the presence of PDGF-BB significantly increased apoptotic cells compared with the control condition. Thus, Akt-I-1/2 could mimic the effects of imatinib on PASMCs. CONCLUSION: Imatinib has anti-proliferative and pro-apoptotic effects on IPAH-PASMCs stimulated with PDGF. The inhibitory effect of imatinib on Akt phosphorylation induced by PDGF plays an important role in the pro-apoptotic effect.

Usefulness of acute pulmonary vasoreactivity test of sildenafil in treatment of portopulmonary hypertension. A case report.

A 50-year-old man diagnosed with liver cirrhosis type C was referred to our hospital because of right heart failure with pulmonary hypertension. Echocardiography revealed enlargement of the right atrium and ventricle with severe tricuspid regurgitation. The peak flow velocity of tricuspid regurgitation by continuous wave Doppler echocardiography was 452 cm/s. Right heart catheterization demonstrated severe pulmonary hypertension [pulmonary arterial pressure (PAP) systolic/diastolic/mean = 73/20/41 mmHg and pulmonary vascular resistance (PVR) = 509 dyn s cm-5] with portal hypertension. We diagnosed the patient as having portopulmonary hypertension (PoPH). Although we treated the patient with a prostacyclin analog, tricuspid regurgitation velocity was increased to 480 cm/s four years after the start of the therapy. To select drugs for the treatment of PoPH, we performed an acute vasoreactivity test of sildenafil during right heart catheterization. Since single administration of sildenafil (20 mg) decreased PAP (93/30/55-77/27/44 mmHg) and PVR (908-833 dyn s cm-5), we added sildenafil (20 mg, t.i.d.) to the prostacyclin analog. Tricuspid regurgitation velocity decreased to 403 cm/s one year after the addition of sildenafil. An acute vasoreactivity test of sildenafil during right heart catheterization was useful for the decision of the drug to be used in the treatment of PoPH.

Clinical features of and effects of angiotensin system antagonists on amiodarone-induced pulmonary toxicity.

BACKGROUND: Amiodarone (AMD) is a strong antiarrhythmic drug but has severe side effects such as pulmonary toxicity. There are no indicators or drugs that can prevent the development of amiodarone-induced pulmonary toxicity (AIPT). METHODS: We collected data for 96 consecutive patients treated with AMD and analyzed clinical factors related to AIPT. In addition, we examined the effect of AMD and angiotensin II (Ang II) on human lung alveolar epithelial cells (AEC) and verified the protective efficacy of an Ang II type 1 receptor blocker (ARB) in vitro. RESULTS: During a follow-up period of 33.8+/-34.6 months, AIPT developed in 11 patients (11.5%). There were no differences in the dose of AMD, left ventricular ejection fraction, serum KL-6 and %DLCO level before starting AMD between patients with and those without AIPT. However, repeated episodes of congestive heart failure (CHF) were observed more frequently in patients with AIPT than in patients without AIPT (81.8% vs. 41.2%, P<0.011). In vitro examination, AMD progressively increased apoptosis of AEC and Ang II enhanced this effect of AMD (P<0.001). However, ARB inhibited the enhancement by Ang II of the AMD-induced apoptosis effect (P<0.001). Furthermore, patients with AIPT were administrated a lower dose of angiotensin system antagonists than were those without AIPT (P<0.05). CONCLUSIONS: The results indicate that Ang II induced by CHF increases the risk of AMD-induced pulmonary toxicity. An angiotensin-converting enzyme inhibitor or ARB should be given at a sufficient dose during AMD treatment.