Yoshito Ogihara

Ventricular function and dyssynchrony quantified by speckle-tracking echocardiography in patients with acute and chronic right ventricular pressure overload.

BACKGROUND The aim of this study was to noninvasively investigate right ventricular and left ventricular (LV) adaptation to right ventricular pressure overload in patients with acute pulmonary thromboembolism (APTE) and chronic pulmonary artery hypertension (CPAH). METHODS Thirty-seven patients with APTE, 36 patients with CPAH, and 33 controls were retrospectively enrolled. Myocardial deformation and wall motion were analyzed using speckle-tracking strain and displacement imaging echocardiography in the right and left ventricles. The standard deviation of the heart rate-corrected intervals from QRS onset to peak systolic strain and peak systolic displacement (PSD) for the six segments was used to quantify right ventricular and LV mechanical dyssynchrony (peak systolic strain dyssynchrony and PSD dyssynchrony). The myocardial performance index in both ventricles was also evaluated. RESULTS The APTE and CPAH groups had reduced ventricular performance (LV myocardial performance index, 0.40 ± 0.10, 0.66 ± 0.18 [P < .05 vs controls], and 0.58 ± 0.19 [P < .05 vs controls] in the control, APTE, and CPAH groups, respectively) and large mechanical dyssynchrony (LV longitudinal PSD dyssynchrony, 58 ± 41 msec, 119 ± 49 msec [P < .05 vs controls], and 83 ± 37 msec [P < .05 vs controls and the APTE group] in the control, APTE, and CPAH groups, respectively) in both ventricles. Multiple regression analysis indicated that LV longitudinal PSD dyssynchrony in the APTE group and the LV eccentricity index in the CPAH group were independent determinants of LV myocardial performance index. CONCLUSIONS Pathophysiologic mechanisms that regulate ventricular performance vary depending on whether the ventricles are exposed to acute or chronic right ventricular pressure overload.

Utility of right ventricular Tei-index for assessing disease severity and determining response to treatment in patients with pulmonary arterial hypertension

BACKGROUND We sought to evaluate the potential utility of echocardiography-derived morphological and functional right ventricular (RV) variables for assessing disease severity of pulmonary arterial hypertension (PAH) and determining the changes in the patients hemodynamics in the clinical course. METHODS AND RESULTS This study consisted of 24 normal controls (the control group) and 24 patients with PAH at rest or with exercise (the PAH group) who underwent echocardiography, right heart catheterization, plasma brain natriuretic peptide (BNP) measurement, and six-minute walk distance (6MWD) test. The PAH group had poorer RV echocardiographic variables than the control group. RV Tei-index was more strongly correlated with 6MWD, BNP, cardiac index, mean pulmonary arterial pressure, and pulmonary vascular resistance (PVR) than other RV echocardiography-derived variables including RV end-diastolic areas, RV fractional area change, and tricuspid annular plane systolic excursion. In 16 of the 24 patients who successfully underwent repeated examination during follow up (13.3 ± 4.9 months; range, 5-24 months), PVR decreased from 486 ± 380 dynes cm(-5) to 346 ± 252 dynes cm(-5), and RV Tei-index decreased from 0.55 ± 0.30 to 0.42 ± 0.17, and the changes in RV Tei-index were correlated with the concomitant changes in PVR during the clinical course of PAH (r=0.706, p=0.002). Tricuspid annular plane systolic excursion and RV fractional area change did not change during the follow up. CONCLUSIONS Quantitative echocardiography revealed that the measurement of RV Tei-index is of great clinical utility for predicting disease severity of PAH and determining the changes in the patients hemodynamics in the clinical course.

Anti-Xa activity in VTE patients treated with fondaparinux

We previously reported that an anti-Xa level of N 0.33mg/l on day 1 is associated with the risk of withdrawal of fondaparinux due to increased bleeding in patients undergoing major orthopedic surgery with prophylaxis, whereas the anti-Xa levels on day 4 and 8 are not correlated with this risk [1]. The anti-Xa level has been reported to be correlated with weight, height, body mass index and antithrombin activity [2], and the cause of increased bleeding in these patients is suggested to be hyperfibrinolysis [3]. Anti-Xa inhibitors, such as fondaparinux, have been used for prophylaxis as well as treatment in cases of venous thromboembolism (VTE) [4]. However, there are few reports regarding the anti-Xa activity in patients with VTE treated with fondaparinux. Therefore, we examined the Xa activity in 16 patients with deep vein thrombosis (DVT) or pulmonary embolism (PE) treated with fondaparinux. Eleven patients received 7.5 mg of fondaparinux and 5e patients with a low weight or old age received 3 or 5 mg of fondaparinux. No bleeding symptoms were observed among the patients treated with fondaparinux, and the median (95% confidence interval) anti-Xa activity was 1.34 mg/L (0.62– 1.99 mg/L). The anti-Xa activity was not found to correlate with weight or the creatinine level, suggesting that the physicians selected the appropriate dose of treatment in accordance with the patients condition. Both the symptoms and the computed tomography and echography findings improved, and the soluble fibrin and Ddimer levels significantly decreased after the administration of

Detrimental Impact of Vasopressin V2 Receptor Antagonism in a SU5416/Hypoxia/Normoxia-Exposed Rat Model of Pulmonary Arterial Hypertension

BACKGROUND The expression of vasopressin type 2 receptor (V2R) in the lung, and the long-term effects of tolvaptan, a selective V2R antagonist, on pulmonary circulation and right ventricular (RV) remodeling in a pulmonary arterial hypertension (PAH) rat model were evaluated. METHODSANDRESULTS Six-week-old male Sprague-Dawley rats were injected subcutaneously with 20 mg/kg of SU5416 and were exposed to hypoxia for 3 weeks followed by re-exposure to normoxia for 7 weeks. These rats showed signs of RV failure and upregulation of V2R and cAMP in the lung tissue at 10 weeks after SU5416 injection. They were then treated with either 0.05% tolvaptan in diet (SUHx+Tolv) or normal diet (SUHx) during 5-10 weeks of SU5416 injection. Normal control rats (Cont) were also used for comparison. SUHx+Tolv had significantly higher pulmonary arterial pressure, more progressive pulmonary arterial remodeling, and more severe myocyte hypertrophy and interstitial myocardial fibrosis in the right ventricle compared with SUHx despite achieving successful preload reduction. CONCLUSIONS Chronic vasopressin V2R antagonism may contribute to the worsening of PAH and the development of RV remodeling.

Renal papillary tip extract stimulates BNP production and excretion from cardiomyocytes

Background Brain natriuretic peptide (BNP) is an important biomarker for patients with cardiovascular diseases, including heart failure, hypertension and cardiac hypertrophy. It is also known that BNP levels are relatively higher in patients with chronic kidney disease and no heart disease; however, the mechanism remains unclear. Methods and results We developed a BNP reporter mouse and occasionally found that this promoter was activated specifically in the papillary tip of the kidneys, and its activation was not accompanied by BNP mRNA expression. No evidence was found to support the existence of BNP isoforms or other nucleotide expression apart from BNP and tdTomato. The pBNP-tdTomato-positive cells were interstitial cells and were not proliferative. Unexpectedly, both the expression and secretion of BNP increased in primary cultured neonatal cardiomyocytes after their treatment with an extract of the renal papillary tip. Intraperitoneal injection of the extract of the papillary tips reduced blood pressure from 210 mmHg to 165 mmHg, the decrease being accompanied by an increase in serum BNP and urinary cGMP production in stroke-prone spontaneously hypertensive (SHR-SP) rats. Furthermore the induction of BNP by the papillary extract from rats with heart failure due to myocardial infarction was increased in cardiomyocytes. Conclusions These results suggested that the papillary tip express a substance that can stimulate BNP production and secretion from cardiomyocytes.

Effects of low-dose tolvaptan on electrolyte abnormality and hemodynamic parameters in a liver cirrhosis-associated portopulmonary hypertension patient: A case report

The present study reported a case of portopulmonary hypertension (POPH) that was secondary to underlying liver cirrhosis in a 58-year-old woman, who was successfully treated with low-dose tolvaptan. The patient had suffered from refractory peripheral edema and electrolyte abnormalities, including severe hypokalemia, under the combination therapy of sildenafil, ambrisentan, furosemide and spironolactone. Subsequent to the initiation of low-dose tolvaptan at 3.75 mg/day with concurrent de-escalation of the dose of furosemide, the daily urine volume increased, peripheral edema improved and the serum potassium level increased immediately. In addition, plasma renin activity, plasma aldosterone concentration and plasma brain natriuretic peptide level decreased within 1 week after the initiation of tolvaptan therapy. Hemodynamic assessments using a right heart catheter revealed that the pulmonary vascular resistance decreased by ~20%. Finally, chronic combination therapy with spironolactone and low-dose tolvaptan without loop diuretics achieved adequate fluid management. In conclusion, the findings of the present study suggest that low-dose tolvaptan may be a promising therapeutic option for liver cirrhosis-associated POPH in patients with an electrolyte abnormality due to liver cirrhosis and conventional diuretics.

Incidence, Characteristics and Management of Venous Thromboembolism in Japan During 2011

BACKGROUND This study aimed to determine the incidence, characteristics and management of venous thromboembolism (VTE) in Japan during 2011.Methods and Results:A retrospective study assessed responses to a questionnaire regarding treating newly diagnosed VTE at all admitting hospitals throughout Japan during 2011. More individuals were diagnosed with VTE than ever before, with 16,096 cases of diagnosed pulmonary embolism (PE) and 24,538 cases of diagnosed deep vein thrombosis (DVT). Almost half (47.2%) of the PE patients had a relatively mild condition with no right ventricular overload. Similarly, almost half (43.8%) of the DVT patients had a relatively mild condition with isolated calf thrombus. Most of PE patients were treated by anticoagulation, and fewer were treated using thrombolytic agent or inferior vena cava (IVC) filter. CONCLUSIONS The present study showed a remarkable increase in the incidence of VTE in Japan during 2011. Relatively mild conditions such as non-massive PE and isolated calf DVT were frequently diagnosed. Among PE patients, thrombolytic therapy or IVC filter implantation decreased compared with previous surveys. The appropriate management of isolated calf DVT requires further investigation.

Pulse-spray catheter-directed thrombolysis with urokinase and argatroban for thrombo-occlusion of an inferior vena cava filter due to heparin-induced thrombocytopenia with thrombosis

A 50-year-old man developed acute sub-massive pulmonary thromboembolism and proximal deep venous thrombosis. A continuous intravenous infusion of unfractionated heparin (UFH) was started, and an inferior vena cava (IVC) filter was implanted. He developed symptomatic complete obstruction of the filter 6 days after the initiation of UFH, and he was transferred to our hospital. We started pulse-spray catheter-directed thrombolysis (CDT) with urokinase. However, thrombocytopenia occurred 11 days after the initiation of heparin. We suspected heparin-induced thrombocytopenia (HIT) with thrombosis (HITT), and switched from UFH to argatroban. In addition, we continued pulse-spray CDT. As a result, thrombocytopenia improved and thrombolysis was successful without complications of recurrent thromboembolism or bleeding, leading to retrieval of the IVC filter. The antigen assay for HIT was strongly positive, supporting our diagnosis. In patients with suspected HIT it is important to switch from heparin to an alternative anticoagulant as soon as possible, and pulse-spray CDT with urokinase and argatroban as anticoagulant therapy may be effective treatment for thrombo-occlusions of IVC filters in patients with HITT. <Learning objective: Thrombo-occlusion is a serious complication of inferior vena cava filters. Anticoagulant therapy alone is not effective for dissolving thrombo-occlusions of inferior vena cava filters. In patients with heparin-induced thrombocytopenia with thrombosis, pulse-spray catheter-directed thrombolysis with urokinase and argatroban as anticoagulant therapy may be effective treatment for venous thrombo-occlusion.>.