Koichiro Kinugawa

Urine Aquaporin-2: A Promising Marker of Response to the Arginine Vasopressin Type-2 Antagonist, Tolvaptan in Patients with Congestive Heart Failure

Aquaporin-2, a member of the aquaporin family, is an arginine vasopressin-regulated water channel expressed in the renal collecting duct, and a promising marker of the concentrating and diluting ability of the kidney. The arginine vasopressin type-2 antagonist, tolvaptan, is a new-generation diuretic; it is especially indicated in patients with decompensated heart failure refractory to conventional diuretics. However, the ideal responders to tolvaptan have not yet been identified, and non-responders experience worse clinical courses despite treatment with tolvaptan. Urine aquaporin-2 has recently been demonstrated as a promising predictor of response to tolvaptan. We here validated aquaporin-2-guided tolvaptan therapy in patients with decompensated heart failure. Long-term efficacy of tolvaptan treatment in the responders defined by aquaporin-2 needs to be validated in the future prospective study.

Waon Therapy for Managing Chronic Heart Failure – Results From a Multicenter Prospective Randomized WAON-CHF Study –

BACKGROUND Waon therapy improves heart failure (HF) symptoms, but further evidence in patients with advanced HF remains uncertain. METHODSANDRESULTS In 19 institutes, we prospectively enrolled hospitalized patients with advanced HF, who had plasma levels of B-type natriuretic peptide (BNP) >500 pg/ml on admission and BNP >300 pg/ml regardless of more than 1 week of medical therapy. Enrolled patients were randomized into Waon therapy or control groups. Waon therapy was performed once daily for 10 days with a far infrared-ray dry sauna maintained at 60℃ for 15 min, followed by bed rest for 30 min covered with a blanket. The primary endpoint was the ratio of BNP before and after treatment. In total, 76 Waon therapy and 73 control patients (mean age 66 years, men 61%, mean plasma BNP 777 pg/ml) were studied. The groups differed only in body mass index and the frequency of diabetes. The plasma BNP, NYHA classification, 6-min walk distance (6MWD), and cardiothoracic ratio significantly improved only in the Waon therapy group. Improvements in NYHA classification, 6MWD, and cardiothoracic ratio were significant in the Waon therapy group, although the change in plasma BNP did not reach statistical significance. No serious adverse events were observed in either group. CONCLUSIONS Waon therapy, a holistic soothing warmth therapy, showed clinical advantages in safety and efficacy among patients with advanced HF.

Ratio of urine and blood urea nitrogen concentration predicts the response of tolvaptan in congestive heart failure

This study was conducted to evaluate the performance of the ratio of urine and blood urea nitrogen concentration (UUN/BUN) as a new predictive factor for the response of an arginine vasopressin receptor 2 antagonist tolvaptan (TLV) in decompensated heart failure patients.

Tolvaptan Prolongs Blockage of the Vasopressin Type II Receptor Over 24 Hours in Responders With Stage D Heart Failure.

The urine aquaporin-2 (U-AQP2) level relative to the plasma arginine vasopressin (P-AVP) level is a novel predictor of the responsiveness to the vasopressin type 2 receptor (V2R) antagonist tolvaptan (TLV). However, little has been reported about the concentration-time profile of U-AQP2 after TLV treatment. We evaluated 24 patients with decompensated stage D heart failure (HF) who had received 3.75 mg/day of TLV on a de novo basis for > 7 days to treat congestion refractory to conventional diuretics. Seventeen patients were TLV-responders, whose 24-hour urine volume (UV) increased after TLV initiation; the other 7 patients were TLV-non-responders. The U-AQP2 of the TLV-responders, corrected for the urine creatinine concentration, decreased significantly at 4 hours after TLV administration without returning to the day-1 morning level on the morning of day-7. The TLV-non-responder U-AQP2 levels remained low even before the TLV treatment. On the morning of day-7, the TLV-responder U-AQP2/P-AVP ratio was comparable to that of the TLV-non-responders. Among 18 patients (11 responders and 7 non-responders), the day-7 TLV trough concentration was 64 ± 62 ng/mL and was negatively correlated with the estimated glomerular filtration rate (eGFR). TLV has antagonistic effects on the V2R over 24 hours in TLV-responders with advanced heart failure and chronic kidney disease, probably due to persistently elevated blood TLV concentration. The unresponsiveness to TLV in the TLV-non-responders is not attributable to malabsorption.

Tolvaptan Reduces Long-Term Total Medical Expenses and Length of Stay in Aquaporin-Defined Responders.

The vasopressin type-2 antagonist tolvaptan (TLV) has clinical advantages including amelioration of congestion and normalization of hyponatremia in patients with decompensated heart failure (HF). However, there have been no studies on the cost-effectiveness of TLV therapy. We enrolled 60 consecutive hospitalized patients with stage D HF who received TLV [TLV (+) group], and 60 propensity score-matched HF patients without TLV treatment [TLV (-) group]. We excluded 54 patients who died or received cardiac replacement therapy within 1 year, and finally enrolled 32 patients who received TLV and 34 who did not, who were followed for > 1 year. Among 45 aquaporin-defined responders, whose urine aquaporin-2 relative to plasma arginine vasopressin level was > 1.4 × 10(3) L/g Cre, the TLV (+) group required significantly lower total medical expenses and shorter lengths of stay (LOS) compared with the TLV (-) group [11.2 (1.233.3) versus 31.2 (2.2-71.4) × 10(5) JPY/year, P < 0.001; 30 (0-304) versus 70 (20-221) days, P = 0.030]. In contrast, among the remaining 21 aquaporin-defined non-responders, medical expenses and LOS were comparable irrespective of TLV administration (P = 0.087 and P = 0.407). In conclusion, TLV therapy may reduce total medical expenses in aquaporin-defined responders with stage D HF.

Tolvaptan Improves the Long-Term Prognosis in Patients With Congestive Heart Failure With Preserved Ejection Fraction as Well as in Those With Reduced Ejection Fraction.

Tolvaptan (TLV), an arginine vasopressin type 2 antagonist, has been shown to play a role in ameliorating symptomatic congestion and normalizing diluted hyponatremia in patients with congestive heart failure (HF). However, most evidence was derived from patients with HF with reduced ejection fraction (HFrEF), and the clinical efficacy of TLV in patients with HF with preserved ejection fraction (HFpEF) remains uncertain. In this study, we retrospectively enrolled 60 in-hospital patients with stage D HF, who had received TLV to treat symptomatic congestion at our institute between 2011 and 2013. As a control group, we also enrolled 60 background-matched HF patients who did not receive TLV therapy. Patients with HFpEF (n = 29), whose left ventricular ejection fraction was > 45%, had higher age and a lower urine aquaporin-2 level relative to the plasma arginine vasopressin concentration compared with those with HFrEF (n = 91). TLV therapy significantly reduced the 2-year readmission rates in both the HFrEF and HFpEF populations (P < 0.05 for both), indicating that TLV therapy may improve the long-term prognosis not only in patients with HFrEF but also in those with HFpEF.

Sympathetic Nerve Activity Efferent Drive and Beta-Blocker Treatment – Effect of Interaction in Systolic Heart Failure –

BACKGROUND Although both β-blocker dose (BBD) and sympathetic activity efferent drive are associated with prognosis in chronic heart failure (HF), little is known about the prognostic value of the interaction between them. METHODSANDRESULTS Potential prognostic variables including resting muscle sympathetic nerve activity (MSNA) were investigated in 133 patients with HF (ejection fraction [EF] <0.45). BBD was normalized to therapeutically equivalent doses of carvedilol. Primary cardiovascular endpoints included cardiovascular death and HF hospitalization. Predictors for outcomes were assessed on univariate, multivariate, and Kaplan-Meier analysis. EF was followed for 9 months after MSNA measurement in 102 patients. During the 1,419±824-day follow-up period, 24 patients died (sudden death, n=10; progressive HF, n=14). On multivariate Cox proportional hazard analysis, higher MSNA (P=0.037; HR, 2.01) and lower BBD (<5.0 mg/day; P=0.041; HR, 1.94) were independent predictors of cardiovascular events. Patients were divided into higher MSNA (≥64 bursts/100 beats) and lower MSNA groups. Although lower BBD remained an independent predictor in patients with higher MSNA, BBD was not statistically significant in patients with lower MSNA on univariate analysis. Additionally, there was a lower EF change in patients with lower BBD and higher MSNA. CONCLUSIONS Higher BBD might be necessary to avoid cardiovascular events in HF patients with central sympathetic overactivation. (Circ J 2016; 80: 2149-2154).

Right Ventricular End-Diastolic Pressure Is a Key to the Changes in Cardiac Output During Adaptive Servo-Ventilation Support in Patients With Heart Failure

Adaptive servo-ventilation (ASV) is a recently-developed non-invasive therapy that improves the clinical course of heart failure (HF) patients. However, the precise hemodynamic response and predictors of ASV therapy remain uncertain. Overall, 69 patients with New York Heart Association HF class II-IV underwent 10-minute ASV testing along with hemodynamic studies. Among them, 21 (30%) achieved an acute response, which was defined as an increase in the cardiac index (CI) during ASV. ΔLeft ventricular end-diastolic pressure (LVEDP) did not correlate with ΔCI, whereas Δtransmural LVEDP, which was calculated by subtracting right ventricular end-diastolic pressure (RVEDP) from LVEDP, and ΔCI were positively correlated, similar to the ascending limb of Frank-Starlings law (P = 0.009, r = 0.311). Among baseline data, higher RVEDP and higher LVEDP were significant predictors of an acute response by logistic regression analyses (P < 0.05 for both). RVEDP had a significantly higher area under the curve than LVEDP in the receiver operating characteristic analyses (0.846 versus 0.673, P = 0.028). Higher baseline RVEDP was significantly associated with a greater decrease in RVEDP during ASV (P < 0.001, r = -0.604). In conclusion, in HF patients with elevated RVEDP, ASV increased cardiac output through a decrease in RVEDP and an increase in transmural LVEDP, according to the ascending limb of Frank-Starlings law.

Successful Pregnancy and Delivery in a Heart Transplantation Recipient

For 6 years after heart transplantation, a 23-year old female recipient had been treated with immunosuppressants including tacrolimus and mycophenolate mofetil (MMF), without any major rejection or graft dysfunction. She unexpectedly became pregnant for the first time, and we converted MMF to azathioprine (AZA), but she soon experienced a spontaneous abortion. After careful counseling under the continuation of AZA, she became pregnant again 3 months after the abortion. We closely monitored the concentration of immunosuppressive agents, cardiac function, fetal condition, and serological assay including human leukocyte antigen (HLA) sensitization, and she eventually delivered a normal male infant at 38 weeks gestation without any complications. AZA was converted to MMF soon after the delivery. There have been no complications in either the patient or infant after the delivery.Because pregnancy itself involves a risk of cardiac graft rejection in the recipient as well as fetal complications, it is important to educate HTx recipients about planned pregnancy and to conduct careful follow-up after pregnancy.

Real-Time Assessment of Autonomic Nerve Activity During Adaptive Servo-Ventilation Support or Waon Therapy

Adaptive servo-ventilation support and Waon therapy are recently developed non-pharmacological and noninvasive therapies for patients with heart failure refractory to guideline-directed medical therapy. These therapies decrease both preload and afterload, increase cardiac output, and appear to ameliorate autonomic nerve activity. However, the time course of autonomic nerve activity during these therapies remains unclear. We performed heart rate variability analysis using the MemCalc power spectral density method (MemCalc system; Suwa Trust Co, Tokyo) to assess autonomic nerve activity during adaptive servo-ventilation support and Waon therapy in two different cases and determined the time course of autonomic nerve activity during these therapies. During both therapies, we found a drastic increase in parasympathetic nerve activity and continuous suppression of sympathetic nerve activity. Heart rate variability analysis using the MemCalc method may be promising for the assessment of the efficacy of various treatments, including adaptive servo-ventilation support and Waon therapy, from the viewpoint of autonomic nerve activity.