An Exploratory Study of Dapagliflozin for the Attenuation of Albuminuria in Patients with Heart Failure and Type 2 Diabetes Mellitus (DAPPER).

BACKGROUND AND AIMS: Sodium-dependent glucose transporter-2 (SGLT-2) inhibitors, which are anti-diabetic drugs, reportedly decrease the incidence of cardiovascular events in high-risk patients with cardiovascular diseases, and thus chronic heart failure (CHF). SGLT-2 inhibitors also decrease albuminuria in patients with type 2 diabetes mellitus (T2D). Since albuminuria is a biomarker of not only chronic kidney disease but also cardiovascular events, we hypothesized that, among T2D patients with CHF, SGLT-2 inhibitors will decrease the extent of albuminuria and also improve CHF concomitantly. METHODS: DAPPER (UMIN000025102) is a multicenter, randomized, open-labeled, parallel-group, standard treatment-controlled study, which is designed to evaluate whether dapagliflozin, one of the SGLT-2 inhibitors, decreases albuminuria in T2D patients with CHF and exerts cardioprotective effects on the failing heart. The patients are randomized to either of the dapagliflozin (5 or 10 mg, once daily orally) or control group (administration of anti-diabetic drugs administered other than SGLT 2 inhibitors). The estimated number of patients that need to be enrolled is 446 in total (223 in each group). The primary objective is the changes in the urinary albumin-to-creatinine ratio from the baseline after 2-year treatment. The key secondary objectives are (1) the safety of dapagliflozin and (2) the cardiovascular and renal efficacies of dapagliflozin. CONCLUSION AND PERSPECTIVES: DAPPER study investigates whether dapagliflozin decreases albuminuria and exerts beneficial effects on the failing heart in T2D patients. (UMIN000025102).

The Effect of Continuous Renal Replacement Therapy with the AN69ST Membrane on Inflammatory Markers and the Level of Consciousness of Hemodialysis Patients with Stroke: Comparison with Hemodialysis with Low Blood Flow Rate.

INTRODUCTION: Hemodialysis (HD) with low blood flow rate, continuous renal replacement therapy (CRRT), and peritoneal dialysis are recommended for patients with stroke complications to prevent intracranial hypertension because of the low diffusion capacity of the brain barrier. However, detailed guidelines are not currently available; thus, there is an urgent need to establish such guidelines. MATERIAL AND METHODS: We developed a novel protocol for performing CRRT with the AN69ST membrane, which has excellent adsorption capacity for various cytokines. The objective of this study was to compare the effect of the novel protocol with that of the current standard protocol, i.e. hemodialysis with low blood flow rate. To compare the effect of hemodialysis with low blood flow (HD group, n=27) and CRRT with AN69ST membrane (CRRT group, n=8), we measured the following consciousness and blood inflammatory parameters in patients with stroke complications at baseline and after 1 week of treatment: Glasgow Coma Scale (GCS) score, C-reactive protein (CRP) levels, and white blood cell (WBC) and platelet count. RESULTS: After 1 week, the total GCS score did not improve in the HD group, but improved significantly in the CRRT group (HD group: 13.1±3.0 to 13.3±3.1, p=0.5508, CRRT group: 8.9±3.9 to 11.5±3.9, p=0.0313). Improvement in the CRRT group was significantly higher than in the HD group (p=0.0039). CRP levels did not change significantly in either the HD (3.8±5.5 to 5.3±4.3 n.s.) or CRRT groups (7.7±10.0 to 3.7±3.2 n.s.); however, they tended to increase in the HD group and decrease in the CRRT group. No significant changes were observed in WBC and platelet counts after 1 week of treatment in either group. CONCLUSION: CRRT with the AN69ST membrane might have a beneficial effect on the consciousness level and inflammation of patients with stroke.

Plasma B-type natriuretic peptide is a useful tool for assessing coronary heart disease risk in a Japanese general population.

B-type natriuretic peptide (BNP) has been reported to be associated with cardiovascular prognosis in a community-based population. In addition, accumulation of individual cardiovascular risk factors is important in predicting an individual's risk of future cardiovascular disease. However, there have been few reports showing that BNP is a comprehensive marker of the accumulation of cardiovascular risk factors. We studied 1530 community-dwelling subjects without obvious heart diseases or renal dysfunction (mean age 62 ± 15 years; 569 men and 961 women) who participated in an annual health checkup in a rural Japanese community. Coronary heart disease (CHD) risk was estimated, and patients were placed into the following three groups based on the Framingham function: low risk, moderate risk and high risk. The prevalence of moderate- and high-risk subjects for CHD rose in both genders with increasing plasma BNP levels. The area under the receiver operating characteristic curve showed a modest ability of plasma BNP levels to detect these subjects (0.755 and 0.700 for men and women, respectively). The optimal thresholds for the identification of subjects with moderate- and high-risk disease were BNP concentrations of 12.0 and 22.0 pg ml(-1), with sensitivities of 70% and 66% and specificities of 71% and 63% for men and women, respectively. In conclusion, subjects with high plasma BNP levels were at higher risk for CHD in a population without obvious heart disease or renal dysfunction.

Dynamic changes in plasma total and high molecular weight adiponectin levels in acute heart failure.

BACKGROUND: Elevated levels of total plasma adiponectin (APN) and high molecular weight (HMW)-APN have been observed in chronic heart failure (HF) and are associated with poor prognosis, however, the response of APN levels in acute HF is not known. The purpose of this study was to clarify the dynamic changes of the plasma total APN, HMW-APN levels, and the ratio of HMW-APN to total APN (HMWR) in acute HF. METHODS: From February 2006 to January 2007, 20 patients with acute HF (non-ischemic and non-valvular origin, 17 men, aged 63±11 years) were enrolled, and blood was sampled before the onset of the treatment and at discharge. Ten patients admitted for the treatment of supraventricular arrhythmia (8 men, aged 45±13 years) were included as controls. RESULTS: The medians and interquartile ranges of the plasma total APN, HMW-APN levels, and HMWR at admission were 20.8 (14.5-38.9) µg/mL, 12.4 (7.7-23.3) µg/mL, and 0.60 (0.50-0.69), respectively. The total APN and HMW-APN values were significantly higher than the values of the control. The plasma total APN, HMW-APN, and HMWR values at discharge decreased to 19.4 (7.2-27.3)µg/mL, 10.5 (3.2-12.8) µg/mL, and 0.52 (0.46-0.57), respectively. An exploratory survival analysis showed that the higher HMWR values at admission and the larger decrease in HMWR were associated with a better prognosis after discharge. CONCLUSION: Plasma total APN and HMW-APN values are elevated at the admission for acute HF. Plasma total APN, HMW-APN, and HMWR values decrease following treatment. Higher HMWR at admission and its larger decrease may be the signs of favorable treatment responsiveness in acute HF.

Pre- and post-operative risk factors associated with cerebrovascular accidents in patients supported by left ventricular assist device. -Single center's experience in japan-.

BACKGROUND: Cerebrovascular accident (CVA) is a major adverse event following left ventricular assist device (LVAD) surgery. This study investigates pre- and post-operative factors associated with CVA in this population. METHODS AND RESULTS: A total of 118 consecutive patients who underwent LVAD surgery at our institution between April 1994 and April 2009 were retrospectively reviewed. Clinical characteristics, hemodynamic data, and laboratory indexes associated with CVA after LVAD surgery were analyzed. In total, 57 (48.3%) patients developed CVA 133.5 ± 184.7 days after surgery. The combination of baseline heart disease, type of LVAD surgery, mean right atrial pressure (mRA), serum total bilirubin and total protein concentration, and right ventricular end-diastolic dimension (RVEDd) was associated with CVA at any time after LVAD surgery, with a discriminant probability of 718%. With regard to CVA development later than 3 months after surgery, the combination of mRA and RVEDd before surgery [odds ratio (OR), 1.24, 1.20; 95% confidential interval (CI), 1.07-1.42, 1.06-1.34; P = 0.004, P = 0.006, respectively], positive blood culture, and C-reactive protein after surgery (OR, 7.66, 2.19; 95%CI, 1.50-39.0, 1.47-3.25; P = 0.015, P < 0.0001, respectively) was associated with CVA with a discriminant probability of 85.9%. CONCLUSIONS: Patients' general condition including malnutrition, in addition to device selection, contributed to overall CVA development after surgery. In the chronic phase after surgery, pre-LVAD right heart failure and post-LVAD systemic infection were highly associated with CVA development.

Utility of echocardiographic evaluation of donor hearts upon the organ procurement for heart transplantation.

BACKGROUND: Evaluating donor heart as accurately as possible upon the organ procurement would help lead careful post-transplant heart management. Our institution (National Cerebral and Cardiovascular Center, Osaka, Japan) has sent a transplant cardiologist upon the organ procurement for evaluating a donor heart ever since our first case of heart transplantation. METHODS: Thirteen consecutive bedside echocardiograms obtained from donors upon the organ procurement and post-transplant echocardiograms obtained from their recipients were retrospectively reviewed. The impact of donor echocardiograms on their recipients' post-transplant time course was analyzed and both the donor echocardiographic parameters and their recipients' parameters within 1 week after the heart transplant were compared. RESULTS: Both the left ventricular end-diastolic diameter and the ventricular wall thickness of donors correlated well with those parameters of their corresponding recipients (r(2)=0.740, p<0.0001, r(2)=0.704, p<0.0001, respectively). The information on coronary flow of the donor heart with risk factors for ischemic heart disease was useful for judging the availability for heart transplantation. The information on the pre-existing localized wall motion abnormality of donor hearts was useful for ruling out a possibility of rejection and other causes of wall motion abnormality after transplantation. The mean time required for bedside echocardiography for the donor heart was only 3.7 min. None of the recipients either developed primary graft failure or required treatment for cellular rejection. CONCLUSIONS: Detailed observation of donor hearts by bedside echocardiograms upon the organ procurement is of clinical benefit.

Impact of reduced left atrial functions on diagnosis of paroxysmal atrial fibrillation: results from analysis of time-left atrial volume curve determined by two-dimensional speckle tracking.

BACKGROUND: Atrial fibrillation is commonly associated with impaired reservoir and booster functions of the left atrium (LA). Recent advances in two-dimensional speckle tracking technique (2DST) enabled automatic analysis of the time-LA volume curve representing these functions. Our objective was to evaluate LA function in patients with or without paroxysmal atrial fibrillation (PAF) using 2DST. METHODS: We studied 111 patients (68 men, age 62 ± 16 years) with (n = 53) or without (n = 58) PAF. After constructing time-LA volume curves from the apical four and two chamber views (iE33, Philips with QLAB 6.0, Philips Medical Systems, Bothell, WA, USA), maximal LA volume (LAVmax), preatrial contraction LA volume (LAVpreA), and minimum LA volume (LAVmin) were obtained. Then, LA reservoir volume (ARV=LAVmax-LAVmin) and active emptying volume (AEV=LAVpreA-LAVmin) were calculated to determine ARV/LAVmax as reservoir function and AEV/LAVpreA as booster pump function. RESULTS: PAF was associated with greater LAVmax than that in controls (80 ± 21 ml versus 65 ± 16 ml, p < 0.001) and with reduced reservoir and booster functions (ARV/LAVmax 46 ± 9% versus 52 ± 7%; AEV/LAVpreA 29 ± 10% versus 36 ± 6%, p < 0.001). Multivariate logistic analysis demonstrated that ARV/LAVmax and AEV/LAVpreA were closely associated with the existence of PAF. CONCLUSION: These results demonstrate that the present 2DST enables determining LA reservoir and booster functions, providing insights into the diagnosis of PAF.

Utility of left ventricular systolic torsion derived from 2-dimensional speckle-tracking echocardiography in monitoring acute cellular rejection in heart transplant recipients.

BACKGROUND: Reduced left ventricular torsion (LV-tor) has been reported to be associated with acute rejection in heart transplant (HTx) recipients. We investigated the utility of LV-tor analysis derived from 2-dimensional speckle-tracking echocardiography (2D-STE) for detecting allograft rejection. METHODS: A total of 301 endomyocardial biopsies (EMBs), right heart catheterizations and echocardiograms were performed in 32 HTx recipients. Echocardiography was done within 3 hours from EMB or simultaneously with the procedures. The LV-tor was defined as the difference between apical and basal end-systolic rotations. The LV-tor values with and without cellular rejection were compared. In addition, we investigated whether the change in LV-tor values predicts the change in rejection grade in each patient. The baseline LV-tor value in each patient was defined as a mean value of the first 3 LV-tor measurements obtained when the patient was free from rejection. RESULTS: According to the conventional International Society for Heart and Lung Transplantation criteria, 274 biopsies showed a rejection Grade of 0, 1a or 1b (Group AR(-)), whereas 27 biopsies were Grade 2 or higher (Group AR(+)). LV-tor decreased more in Group AR(+) than in Group AR(-) (9.3 ± 0.7 vs 12.2 ± 0.2 degrees, p < 0.0001). In the LV-tor measurement for each patient, the 25% reduction in LV-tor value from baseline predicted Grade 2 or higher rejection with a predictive accuracy of 92.9%. CONCLUSION: LV-tor derived from 2D-STE could be of clinical value for non-invasive monitoring of acute rejection in HTx recipients.

Cumulative episodes of rejection altered myocardial sarcoplasmic reticulum Ca(2+)-ATPase and ryanodine receptor-2 mRNA expression in heart transplant recipients.

The aim of the present study was to investigate the relationship between rejections and gene expression of Ca(2+)-handling proteins in heart transplant recipients. Thirty-seven heart transplant recipients underwent routine endomyocardial biopsy. Levels of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2) and ryanodine receptor-2 mRNAs in endomyocardial tissue were quantified by a real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) method. Rejections were diagnosed according to the conventional International Society for Heart and Lung Transplantation criteria. Patients were classified as follows; group AR(+) (n = 9) with rejection grade of 2 or higher versus group AR(-) (n = 28) with rejection grade of 0, 1a or 1b at the time of biopsy, and group Rec-AR(+) (n = 6) with a history of more than 4 episodes of treatment required rejection versus group Rec-AR(-) (n = 31) without history of recurrent rejection. The mRNA levels of the SERCA2/GAPDH ratio and ryanodine receptor-2/GAPDH ratio were not different between group AR(+) and group AR(-); however, they were reduced in group Rec-AR(+) more than in group Rec-AR(-) (0.83 +/- 0.07 versus 0.90 +/- 0.07, P = 0.034, 0.74 +/- 0.06 versus 0.84 +/- 0.10, P = 0.027, respectively). A single episode of on-going rejection would not affect myocardial Ca(2+)-handling proteins; however, cumulative rejection episodes might alter the gene expression of myocardial Ca(2+)-handling proteins in heart transplant recipients.

Clinical course and outcome of heart transplant recipients: single center experience at the National Cardiovascular Center in Japan.

The number of heart transplant (HTx) surgeries in Japan is expected to increase under the Revised Organ Transplant Law. To date, among 69 HTx surgeries performed in Japan, 27 operations (39.1%) were performed at our institution, the National Cardiovascular Center (NCVC), located in Osaka. We have reviewed the outcomes of HTx conducted at NCVC during a 10 year period (May 1999 to January 2009). Among 27 heart transplant recipients at NCVC, the clinical charts of 26 recipients whose post-HTx period exceeded 1 year were retrospectively reviewed and compared to data from the International Society for Heart and Lung Transplantation (ISHLT) Registry. The survival rate of our recipients was 96.2% at 10.8 years, which was excellent even compared to the ISHLT Registry. The immunosuppressive regimen at NCVC was equivalent to that of the ISHLT Registry, except for more frequent use of Muromonab-CD3 (26.9% versus 3.3%, P < 0.0001) and an initial CSA-based regimen (65.3% versus 34.4%, P < 0.001). The drug we use for induction therapy has been recently changed from Muromonab-CD3 to Basiliximab. The incidences of post-HTx hypertension, diabetes, hyperlipidemia, and renal insufficiency were significantly less in patients at NCVC compared to those in the ISHLT Registry, however, the incidence of transplant coronary artery disease (TxCAD) was almost identical. Clinical review of post-HTx outcome at NCVC can provide useful information for Japanese transplant cardiologists who will engage in HTx management.

Improved long-term performance of pulsatile extracorporeal left ventricular assist device.

BACKGROUND AND PURPOSE: The majority of heart transplant (HTx) candidates require left ventricular assist device (LVAD) support for more than 2 years before transplantation in Japan. However, the only currently available device is the extracorporeal pulsatile LVAD. The long-term management of extracorporeal LVAD support has improved remarkably over the years. To determine which post-operative management factors are related to the long-term survival of patients on such LVAD, we retrospectively compared the incidence of complications and their management strategies between the initial and recent eras of LVAD use, classified by the year of LVAD surgery. METHODS: Sixty-nine consecutive patients supported by extracorporeal pulsatile LVAD as a bridge to HTx between 1994 and 2007 were reviewed retrospectively. The patients were assigned according to the time of LVAD surgery to either group A (n=30; between 1994 and 2000) or group B (n=39; between 2001 and 2007). RESULTS: Patients in group B survived significantly longer on LVAD support than those in group A (674.6 vs. 369.3 days; p<0.001). The 1- and 2-year survival rates were significantly higher in group B than that in group A (82% vs. 48%, p<0.0001; 68% vs. 23%, p<0.0001, respectively). The proportion of deaths due to cerebrovascular accidents was lower (17% vs. 50%, p<0.001) in group B compared with group A. The incidences of systemic infection were similar in both groups, but the proportions of patients alive and achieving transplant surgery after systemic infection were higher in group B than those in group A (55% vs. 14%, p<0.01; 14% vs. 36%, p<0.05, respectively). CONCLUSIONS: The long-term survival of patients even on "first-generation" extracorporeal LVAD has improved significantly in the recent era. Careful management of cerebrovascular accidents and systemic infection will play important roles in the long-term LVAD management.

Reversible posterior leukoencephalopathy syndrome (RPLS) in a heart transplant recipient treated by substitution of cyclosporine A with tacrolimus.

Reversible posterior leukoencephalopathy syndrome (RPLS) is one of the important adverse events following organ transplantation, associated with calcineurin inhibitors (CNIs). We describe a case of 54-year-old woman, who was diagnosed with RPLS within weeks after transplantation. Considering the risk of causing fatal rejection by discontinuation of CNIs, the immunosuppressive regimen of the patient was switched from a cyclosporine A-based regimen to a tacrolimus-based regimen. The patient recovered rapidly from RPLS following the switch to tacrolimus. This case demonstrated that not only discontinuation but also a substitution of CNIs would be a valid treatment option for RPLS in transplant recipients.

Left atrial volume combined with atrial pump function identifies hypertensive patients with a history of paroxysmal atrial fibrillation.

Identifying patients at high risk for the occurrence of atrial fibrillation is one means by which subsequent thromboembolic complications may be prevented. Left atrial enlargement is associated with progression of atrial remodeling, which is a substrate for atrial fibrillation, but impaired atrial pump function is also another aspect of the remodeling. Our objective was to differentiate patients with a history of paroxysmal atrial fibrillation using echocardiography. We studied 280 hypertensive patients (age: 66+/-7 years; left ventricular ejection fraction: 65+/-8%), including 140 consecutive patients with paroxysmal atrial fibrillation and 140 age- and sex-matched control subjects. Left atrial volume was measured using the modified Simpson method at both left ventricular end systole and preatrial contraction and was indexed to body surface area. Peak late-diastolic mitral annular velocity was measured during atrial contraction using pulsed tissue Doppler imaging as an atrial pump function. Left atrial volume index measured at left ventricular end systole had a 74% diagnostic accuracy and a 71% positive predictive value for identifying patients with paroxysmal atrial fibrillation; these values for the ratio of left atrial volume index at left ventricular end systole to the peak late-diastolic mitral annular velocity were 82% and 81%, respectively, and those for the ratio of left atrial volume index at preatrial contraction to the peak late-diastolic mitral annular velocity were 86% and 90%, respectively. In conclusion, left atrial size combined with atrial pump function enabled a more accurate diagnosis of a history of paroxysmal atrial fibrillation than conventional parameters.

An elderly case of right ventricular outflow obstruction precisely diagnosed and successfully treated with surgical repair.

Congenital diseases causing an obstruction of the right ventricular outflow are difficult to precisely diagnose, especially in elderly patients. Here, we describe a 76-year-old woman who presented to our hospital with shortness of breath on exertion and was finally diagnosed as infundibular pulmonary stenosis by multiple modalities. Surgery was successfully performed and the symptom was relieved. This case underscored the usefulness of multiple modalities for the precise assessment of the right ventricular outflow obstruction and the effectiveness of surgery even in elderly patients with infundibular pulmonary stenosis.

Traumatic tricuspid regurgitation caused by myocardial laceration: a three-dimensional echocardiographic study.

A 19-year-old man was admitted for severe traumatic tricuspid regurgitation (TR) 4 months after a traffic accident. Transthoracic echocardiography revealed severe TR, with an abnormal chordal structure. Three-dimensional echocardiography showed widely lacerated right ventricular endocardium involving many subvalvular components. In this case of traumatic TR, three-dimensional echocardiography was useful not only for its diagnosis but also in providing important information for surgical decision making.

Annual electrocardiograms consistent with silent progression of cardiac involvement in sporadic familial amyloid polyneuropathy: a case report.

Understanding the clinical characteristics of transthyretin familial amyloid polyneuropathy (TTR-FAP) is critical for early diagnosis and timely referral for liver transplantation. Here, we describe a 52-year-old man who had slight paresthesia for four years and whose final diagnosis of TTR-cardiac amyloidosis caused by sporadic FAP was delayed despite annual electrocardiography. Curative liver transplantation was postponed because of progressive cardiac involvement. This experience highlights the difficulties associated with diagnosing TTR-FAP, especially when it is sporadic, and underscores the importance of slight changes in ECG that could indicate FAP.