Tomohiko Ono

Human Pentraxin 3 (PTX3) as a Novel Biomarker for the Diagnosis of Pulmonary Arterial Hypertension

Background Although inflammation is an important feature of pulmonary arterial hypertension (PAH), the usefulness of local inflammatory markers as biomarkers for PAH is unknown. In this study, we tested whether plasma concentrations of human pentraxin 3 (PTX3), a local inflammatory marker, would be a useful biomarker for detecting PAH. Methods Plasma PTX3 concentrations were evaluated in 50 PAH patients (27 with idiopathic PAH, 17 with PAH associated with connective tissue disease (CTD-PAH), and six with congenital heart disease), 100 age and sex-matched healthy controls, and 34 disease-matched CTD patients without PAH. Plasma concentrations of B-type natriuretic peptide (BNP) and C-reactive protein (CRP) were also determined. Results Mean PTX3 levels were significantly higher in all PAH patients than in the healthy controls (4.40±0.37 vs. 1.94±0.09 ng/mL, respectively; P<0.001). Using a threshold level of 2.84 ng/mL, PTX3 yielded a sensitivity of 74.0% and a specificity of 84.0% for the detection of PAH. In CTD-PAH patients, mean PTX3 concentrations were significantly higher than in CTD patients without PAH (5.02±0.69 vs. 2.40±0.14 ng/mL, respectively; P<0.001). There was no significant correlation between plasma levels of PTX3 and BNP or CRP. Receiver operating characteristic (ROC) curves for screening PAH in patients with CTD revealed that PTX3 (area under the ROC curve 0.866) is superior to BNP. Using a PTX3 threshold of 2.85 ng/mL maximized true-positive and false-negative results (sensitivity 94.1%, specificity 73.5%). Conclusion Plasma concentrations of PTX3 may be a better biomarker of PAH than BNP, especially in patients with CTD.

Bone morphogenetic protein receptor type 2 mutations, clinical phenotypes and outcomes of Japanese patients with sporadic or familial pulmonary hypertension

Mutation of bone morphogenetic protein receptor type 2 (BMPR2) is a cause of pulmonary arterial hypertension (PAH). We measured the prevalence of this mutation and its impact on the phenotypes and long‐term clinical outcomes in Japanese patients.

Activation of pyruvate dehydrogenase by dichloroacetate has the potential to induce epigenetic remodeling in the heart

Dichloroacetate (DCA) promotes pyruvate entry into the Krebs cycle by inhibiting pyruvate dehydrogenase (PDH) kinase and thereby maintaining PDH in the active dephosphorylated state. DCA has recently gained attention as a potential metabolic-targeting therapy for heart failure but the molecular basis of the therapeutic effect of DCA in the heart remains a mystery. Once-daily oral administration of DCA alleviates pressure overload-induced left ventricular remodeling. We examined changes in the metabolic fate of pyruvate carbon (derived from glucose) entering the Krebs cycle by metabolic interventions of DCA. (13)C6-glucose pathway tracing analysis revealed that instead of being completely oxidized in the mitochondria for ATP production, DCA-mediated PDH dephosphorylation results in an increased acetyl-CoA pool both in control and pressure-overloaded hearts. DCA induces hyperacetylation of histone H3K9 and H4 in a dose-dependent manner in parallel to the dephosphorylation of PDH in cultured cardiomyocytes. DCA administration increases histone H3K9 acetylation in in vivo mouse heart. Interestingly, DCA-dependent histone acetylation was associated with an up-regulation of 2.3% of genes (545 out of 23,474 examined). Gene ontology analysis revealed that these genes are highly enriched in transcription-related categories. This evidence suggests that sustained activation of PDH by DCA results in an overproduction of acetyl-CoA, which exceeds oxidation in the Krebs cycle and results in histone acetylation. We propose that DCA-mediated PDH activation has the potential to induce epigenetic remodeling in the heart, which, at least in part, forms the molecular basis for the therapeutic effect of DCA in the heart.

The histone 3 lysine 9 methyltransferase inhibitor chaetocin improves prognosis in a rat model of high salt diet-induced heart failure

Histone acetylation has been linked to cardiac hypertrophy and heart failure. However, the pathological implications of changes in histone methylation and the effects of interventions with histone methyltransferase inhibitors for heart failure have not been fully clarified. Here, we focused on H3K9me3 status in the heart and investigated the effects of the histone H3K9 methyltransferase inhibitor chaetocin on prognoses in Dahl salt-sensitive rats, an animal model of chronic heart failure. Chaetocin prolonged survival and restored mitochondrial dysfunction. ChIP-seq analysis demonstrated that chronic stress to the heart induced H3K9me3 elevation in thousands of repetitive elements, including intronic regions of mitochondria-related genes, such as the gene encoding peroxisome proliferator-activated receptor-gamma coactivator 1 alpha. Furthermore, chaetocin reversed this effect on these repetitive loci. These data suggested that excessive heterochromatinization of repetitive elements of mitochondrial genes in the failing heart may lead to the silencing of genes and impair heart function. Thus, chaetocin may be a potential therapeutic agent for chronic heart failure.

Relationship between Digit Ratio and Idiopathic Pulmonary ArterialHypertension in Japanese Women

Aim: Endothelin-1 (ET-1) is the key vasoactive mediator in patients with pulmonary arterial hypertension (PAH), and sex steroids are known to influence ET-1 levels. Additionally, the second to fourth digit (2D:4D) ratio is a biometric marker influenced by testosterone concentrations and androgen receptor sensitivity in the uterus, and some reports have linked (2D:4D) ratio to disease predisposition among patients with gender-dependent conditions. Since idiopathic PAH (IPAH) is more prevalent in women, we hypothesized that the 2D:4D ratio could predict a female’s predisposition to developing PAH, reflecting an interaction between ET-1 and sex hormones. Method: This study analyzed 13 female patients with IPAH at Keio University Hospital and 41 unrelated agematched controls. The right hand of patients and controls was photographed using a digital camera and two experienced scorers measured finger lengths and 2D:4D ratios. Key findings: The IPAH and control groups had a mean age of 43.2 ± 3.5 and 40.9 ± 1.7 years, respectively. The 2D:4D digit ratio was significantly higher for patients with IPAH than for the control women; 0.975 ± 0.041 vs. 0.940 ± 0.038, P<0.05. The age at onset of PAH did not correlate with the ratio. Significance: Female patients with IPAH in this study had a higher 2D:4D digit ratio than age-matched healthy controls, suggesting lower prenatal circulating testosterone levels. In conclusion, the 2D:4D digit ratio is a useful biomarker for IPAH, and prenatal testosterone level could be an important factor for the protection against developing IPAH.

Dual phosphodiesterase type 5 inhibitor therapy for refractory pulmonary arterial hypertension: a pilot study

BackgroundRecent vasodilating drugs have improved prognosis of Pulmonary arterial hypertension (PAH). Some reports describe the merits of combination therapies for PAH, and this study evaluated the efficacy and safety of phosphodiesterase type 5 inhibitors (PDE5i) combination therapy, using sildenafil and tadalafil, for multi-drug-resistant PAH.MethodsWe retrospectively analyzed 7 consecutive refractory patients with PAH administered either sildenafil 60 mg or tadalafil 40 mg as well as both ERA and prostanoid as combination therapies. All were started on the dual PDE5i (sildenafil and tadalafil at maximum dose).ResultsTreatment was generally well tolerated without severe adverse events. On completion of the study, the seven patients received right heart catheterization and the 6-minute walk test (6WMT) 9.6 ± 1.4 months after initiation of the dual PDE5i therapy, showing significant improvements in hemodynamic parameters and exercise tolerance. Mean pulmonary arterial pressure and pulmonary vascular resistance decreased from 47.9 ± 9.7 to 41.7 ± 9.2 mmHg (P = 0.004) and 9.3 ± 2.7 to 6.7 ± 2.9 mmHg (P = 0.018), respectively. Cardiac index and 6MWT also increased from 2.8 ± 0.9 to 3.1 ± 0.8 L/min/m2 (P = 0.026) and 353 ± 60 to 382 ± 62 m (P = 0.014), respectively.ConclusionThe findings support dual PDE5i therapy as a new treatment option for refractory PAH.

Rapid Initiation of Intravenous Epoprostenol Infusion Is the Favored Option in Patients with Advanced Pulmonary Arterial Hypertension

Background Intravenous infusion (IVI) of epoprostenol is an effective treatment for patients with advanced pulmonary arterial hypertension (PAH). However, there is no widely accepted standard method for initiating the IVI therapy. This study evaluated the hemodynamic improvements achieved with IVI epoprostenol to determine the optimal protocol for treatment initiation. Methods and Results We retrospectively analyzed 42 consecutive PAH patients who underwent IVI epoprostenol in Keio University Hospital from 2001 to 2013. The study group comprised 30 women with a mean age of 34.3 ± 1.9 years. The etiology of PAH was idiopathic or heritable PAH (I/HPAH) in 38 cases, PAH associated with connective tissue disease in 3, and Eissenmenger’s syndrome in the remaining case. We divided the patients into rapid- and slow-initiation therapy groups according to the cumulative epoprostenol dose administered during the first 180 days, and compared the hemodynamic changes between the groups. The median cumulative doses were 6142 ± 165 μg/kg and 3998 ± 132 μg/kg epoprostenol, respectively. While there were no significant differences in mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), or cardiac index (CI) between the groups before the IVI epoprostenol therapy, the rapid-initiation therapy group achieved significant improvements in these hemodynamic data compared with the slow-initiation therapy group (P < 0.005) at the follow-up right-heart catheterization (RHC). Conclusion Rapid initiation of IVI epoprostenol therapy achieved the optimal hemodynamic improvements in patients with severe PAH.

Recurrent right atrial thrombosis due to Behçet disease.

Behçet disease is a rare condition sometimes associated with chronic cardiac inflammation followed by myocardial dysfunction and vascular inflammation. We report a case of recurrent right atrial thrombus due to Behçet disease despite continued anticoagulation therapy. The thrombus disappeared after the initiation of immunosuppressive therapy. To avoid a progression to thrombus or cardiac dysfunction in this recurrent case, the early identification of cardiac involvement of Behçet disease using echocardiography and/or cardiac magnetic resonance imaging might be important. Combined immunosuppressive therapy with prednisone and cyclophosphamide might be needed to treat recurrent thrombosis due to Behçet disease.

Temperature variations around medication cassette and carry bag in routine use of epoprostenol administration in healthy volunteers.

Background According to several treatment guidelines, epoprostenol is an important treatment option for pulmonary arterial hypertension. However, the pharmacokinetic characteristics and poor stability of epoprostenol at room temperature make its administration challenging. We therefore studied temperature fluctuations between the drug administration cassette and atmosphere to promote the safe use of epoprostenol. Methods and Findings Five healthy volunteers carried a portable intravenous infusion pump attached to a medication cassette containing saline in a bag during their ordinary activities over 16 days during which the mean atmospheric temperature was 29.6±1.5°C. The temperature around the medication cassette was not less than 25°C on any occasion, and the mean period over 24 h during which the temperature around the cassette exceeded 35°C and 40°C was 96.9±156.4 min and 24.4±77.3 min, respectively. Significant correlations were observed between the temperatures outside the bag and around the cassette, as well as between temperatures around the cassette and of the saline solution in the cassette (r = 0.9258 and 0.8276, respectively). There were no differences in the temperatures outside the bag or around the cassette with respect to the bag material. Conclusions Temperatures around a medication cassette and outside the bag containing the medication increase with sunlight exposure. The temperature around cassettes used for administering epoprostenol must therefore be kept low for as long as possible during hot summer conditions to maintain the drug stability.

Oral vasopressin receptor antagonist tolvaptan in right heart failure due to pulmonary hypertension

During the past decade, the prognosis of patients with pulmonary hypertension (PH) has improved due to the development of pulmonary arterial vasodilators [1]. Yet, treatment for right-sided heart failure (RHF) associated with PH has not improved, despite being the most important prognostic factor for chronic RHF [2, 3]. Existing treatment strategies for RHF associated with PH are restricted to administration of loop diuretics and inotropes [4]; however, administration of high doses of loop diuretics may worsen the outcome of chronic heart failure [5, 6]. In recent years, tolvaptan, an oral, nonpeptide, selective vasopressin V2-receptor antagonist, has been developed for the treatment of hyponatraemia [7], autosomal dominant polycystic kidney disease [8] and heart failure. Used in addition to standard therapy that includes diuretics, tolvaptan improves many signs and symptoms of heart failure without serious adverse events [9]. However, there is no report describing the effect of tolvaptan on RHF, independent of left-sided heart disease. Vasopressin receptor antagonist tolvaptan achieved furosemide reductions and right heart failure improvements in PH http://ow.ly/Lopej