Relationship between the Amount of Menstrual Flow and Cardiac Status in Women with Fontan Circulation.

A high prevalence of heavy menstrual bleeding (HMB) has been reported in women with Fontan circulation. Cyanosis has been reported to contribute to HMB, and menstruation has been suggested to affect cardiac status in women with congenital heart disease. This study aimed to evaluate the relationship between the amount of menstrual flow and cardiac status in women with Fontan circulation.Twenty women who had undergone the Fontan procedure were prospectively investigated and the amount of their menstrual flow was evaluated using a questionnaire. Participants were divided into two groups-small and large menstrual bleeding groups-and their clinical data, including the results of hematological tests and echocardiographic findings, were evaluated.One (5%) woman showed primary amenorrhea. Eight of the remaining 19 (42%) women were included in the large menstrual bleeding group. Women with large menstrual bleeding showed a significantly higher hematocrit level (47.1% [36.2%-50.3%] versus 42.1% [35.3%-44.9%], P = 0.006) and longer QRS duration (106 [92-172] ms versus 88 [78-140] ms, P = 0.008), as well as a lower fractional area change (37.4% [35.6%-47.2%] versus 47.0% [38.2%-55.7%], P = 0.010) and global longitudinal strain (-10.5% [-14.9% to -6.6%] versus -13.9% [-20.5% to -7.8%], P = 0.041) of the dominant ventricle on echocardiography, than women with small bleeding.Erythrocytosis, longer QRS duration, and reduced ventricular function were related to increased menstrual bleeding in women with Fontan circulation. These functions may be interrelated with the amount of menstrual flow in such women.

CRT in a congenital heart disease patient with interventricular dyssynchrony due to an RV conduction delay.

We encountered a unique pattern of cardiac dyssynchrony in a patient with complex congenital heart disease (heterotaxy syndrome) with a biventricular physiology and systemic left ventricle (LV). On speckle tracking echocardiography, dyssynchrony was not detected within the LV, but was noted in an interventricular fashion between the LV and right ventricle (RV). An electrophysiologic study revealed a conduction delay in the subpulmonary RV. Cardiac resynchronization therapy provided reverse cardiac remodeling and an excellent result in our patient by placing the pacing leads around the dyssynchronous lesion.

Evaluating the response to cardiac resynchronization therapy performed with a new ventricular morphology-based strategy for congenital heart disease.

BACKGROUND: In cardiac resynchronization therapy (CRT) for patients with congenital heart disease (CHD) and a ventricular morphology other than a systemic left ventricle (LV), we previously proposed pacing sites that are different from those used for a systemic LV. The leads should be placed laterally on opposite sides of both ventricles in patients with short-axis dyssynchrony and a single ventricular physiology with two ventricles, whereas they should be placed at the farthest sites along the longitudinal direction in the right ventricle (RV) in patients with long-axis dyssynchrony of the RV. Moreover, in patients with interventricular dyssynchrony and a biventricular physiology with a systemic RV, they should be placed at sites that both ventricles can contract simultaneously. We retrospectively investigated 27 consecutive procedures in 24 patients with CHD who underwent CRT to evaluate the effectiveness of a new ventricular morphology-based CRT strategy. The responder rate was 63% (17/27). The reasons for a non-response to CRT in 10 cases were as follows: non-optimal lead positions during CRT, 4; no systemic ventricular conduction delay or heart failure symptoms before the CRT, 5; short follow-up periods after the CRT, 2; and an extremely dilated systemic RV, 1. The responder rate became 88% (14/16), after excluding the procedures without a ventricular conduction delay or heart failure symptoms and those with non-optimal lead positions. This new strategy for CRT can provide favorable results for CHD patients with a systemic ventricular conduction delay and heart failure.

Extremely short setting of optimal sensed atrioventricular interval in patients after Fontan procedure with implanted dual-chamber pacemaker.

BACKGROUND: Atrioventricular interval optimisation is important in patients with dual-chamber pacing, especially with heart failure. In patients with CHD, especially in those with Fontan circulation, the systemic atrial contraction is supposed to be more important than in patients without structural heart disease. METHODS: We retrospectively evaluated two patients after Fontan procedure with dual-chamber pacemaker with a unique setting of optimal sensed atrioventricular interval. RESULTS: The optimal sensed atrioventricular interval determined by echocardiogram was extremely short sensed atrioventricular interval at 25 and 30 ms in both cases; however, the actual P wave and ventricular pacing interval showed 180 and 140 ms, respectively. In both cases, the atrial epicardial leads were implanted on the opposite site of the origin of their own atrial rhythm. The time differences between sensed atrioventricular interval and actual P wave and ventricular pacing interval occurred because of the site of the epicardial atrial pacing leads and the intra-atrial conduction delay. CONCLUSION: We need to consider the origin of the atrial rhythm, the site of the epicardial atrial lead, and the atrial conduction delay by using electrocardiogram and X-ray when we set the optimal sensed atrioventricular interval in complicated CHD.

Living-donor liver transplantation for congenital biliary atresia with porto-pulmonary hypertension and moderate or severe pulmonary arterial hypertension: Kyoto University experience.

Porto-pulmonary hypertension with moderate or severe pulmonary arterial hypertension (PAH) is viewed as a contraindication to liver transplantation (LT) because of associated poor outcomes; however, patients with biliary atresia (BA) are generally good candidates for LT. Ten patients with moderate/severe PAH underwent living-donor liver transplantation (LDLT) at our institution; eight of these patients had BA and were the focus of this study. Preoperative therapies, including prostaglandin (PG)I2 , were introduced. When mean pulmonary arterial pressure (mPAP) after treatment was <40 mmHg or initial mPAP without therapy was <35 mmHg, we performed an acute volume challenge test to evaluate right ventricular function. LDLT was performed when mPAP after anesthetic induction was confirmed at ≤35 mmHg. Six patients had favorable responses to preoperative treatment and catheter testing, but two patients showed poor responses. The two patients with poor responses had poor clinical courses with unstable mPAP after LDLT. The other six patients had successful courses with well-controlled mPAP, and PGI2 was withdrawn or weaned following LDLT. Survival did not significantly differ between the eight BA recipients with moderate/severe PAH and 77 age-matched BA recipients without PAH from the same time period. LDLT has major benefits for BA patients with well-controlled PAH.

Forty-year survival after Glenn procedure without Fontan procedure in patients with single ventricle.

OBJECTIVES: There are no data on long-term outcomes beyond 30 years after the Glenn procedure without the subsequent Fontan procedure in patients with single-ventricle physiology. Hence, this study aimed to clarify the very long-term outcomes of these patients. METHODS: This single-centre, retrospective cohort study investigated the clinical outcomes of patients with single-ventricle physiology who underwent the Glenn procedure between 1970 and 1999. Those who underwent the subsequent Fontan procedure were excluded. The primary outcome was all-cause death. The secondary outcome was a composite of all-cause death, arrhythmic events, neurological events or infective endocarditis. The prognostic factors associated with the long-term outcomes were also evaluated. RESULTS: In total, 36 patients were enrolled (median age at Glenn procedure: 6.2 years, 56% male). During a median follow-up of 17.6 years (interquartile range: 6.1-33.4), 21 patients died and 29 experienced the composite outcome. The 20-, 30- and 40-year overall survival after the Glenn procedure was 51.2%, 44.4% and 40.3%, respectively. The 20-, 30- and 40-year event-free survival was 36.0%, 25.5% and 14.5%, respectively. Patients with dominant left ventricular morphology had better overall survival than those with dominant right ventricular morphology (hazard ratio: 0.24, 95% confidence interval: 0.08-0.76, P = 0.014). None of the patients had liver cirrhosis but 1 had protein-losing enteropathy. CONCLUSIONS: The 40-year overall survival after the Glenn procedure without the subsequent Fontan procedure in patients with single-ventricle physiology was 40.3%. Dominant left ventricular morphology may be associated with better long-term overall survival than dominant right ventricular morphology.

Progressive familial intrahepatic cholestasis: a single-center experience of living-donor liver transplantation during two decades in Japan.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) results in liver cirrhosis. Therefore, some PFIC patients require liver transplantation (LT). Although three types of PFIC have been identified, their etiologies include unknown mechanisms. PATIENTS: A total of 717 recipients who underwent living-donor LT (LDLT) at <20 yr old were enrolled in this study. Among these recipients, 14 PFIC recipients comprising 11 PFIC type 1 (PFIC1) and three PFIC type 2 (PFIC2) were evaluated. RESULTS: Three of 11 PFIC1 recipients died, while all three PFIC2 recipients survived. Eight of 11 PFIC1 recipients showed steatosis after LDLT. Among the eight steatosis-positive PFIC1 recipients, seven showed severe steatosis and seven were complicated with steatohepatitis. Nine of 11 PFIC1 recipients showed fibrosis after LDLT, and eight of the nine fibrosis-positive PFIC1 recipients showed severe fibrosis. In contrast to the PFIC1 recipients, the PFIC2 recipients did not show any steatosis or fibrosis after LDLT. CONCLUSIONS: The clinical courses and outcomes of PFIC1 recipients after LDLT are still not sufficient owing to steatosis/fibrosis, unlike the case for PFIC2 recipients. As PFIC1 patients will require LT during the long-term progression of the disease, further strategy improvements are required for PFIC1 patients.

Long-term outcome of sirolimus-eluting stent implantation for left main coronary artery stenosis in infancy.

Drug-eluting stents (DES) have markedly reduced the incidence of coronary in-stent restenosis. However, DES may be still vulnerable to coronary thrombus, and the long-term outcome remains unknown, especially in infancy. Here, we present a 9-month-old infant, who developed severe stenosis of the left main coronary artery after surgery for Brand-White-Garland syndrome, and was successfully treated with DES. He was healthy and his cardiac function had improved to the normal level at 6 years old. An angiographic examination and computed tomography showed the complete persistence of DES and no evidence of intimal thickening.

Relationship between right and left ventricular diastolic dysfunction assessed by 2-dimensional speckle-tracking echocardiography in adults with repaired tetralogy of Fallot.

Several studies have reported a correlation between right ventricular (RV) and left ventricular (LV) systolic dysfunction in adults with repaired tetralogy of Fallot (TOF). However, data are lacking regarding the relationship between RV and LV diastolic dysfunction assessed by 2-dimensional speckle-tracking echocardiography. We studied 69 adults with repaired TOF (mean age 34 years, 61% male) who had been regularly followed up and had routinely undergone echocardiography. In addition to conventional echocardiography, global longitudinal strain (GLS) and early diastolic strain rate (SRe) of both ventricles were assessed using 2-dimensional speckle-tracking echocardiography. Results were compared with 30 age- and sex-matched controls. RV and LV GLS were decreased in TOF patients compared with controls (- 18.4 ± 3.3% vs. -23.5 ± 4.2%, p < 0.001 and - 16.0 ± 3.8% vs. -20.0 ± 3.0%, p < 0.001, respectively). RV and LV SRe were also decreased in TOF patients compared with controls (1.22 ± 0.34 sec- 1 vs. 1.47 ± 0.41 sec- 1, p = 0.003 and 1.29 ± 0.42 sec- 1 vs. 1.63 ± 0.42 sec- 1, p < 0.001, respectively). A correlation between RV and LV SRe was found in TOF patients (r = 0.43, p < 0.001) as well as between RV and LV GLS (r = 0.45, p < 0.001). Two-dimensional speckle-tracking echocardiography reveals subclinical RV and LV diastolic dysfunction in adults with repaired TOF. A correlation is observed between RV and LV diastolic dysfunction as well as between RV and LV systolic dysfunction.

Neonatal mouse testis-derived multipotent germline stem cells improve the cardiac function of acute ischemic heart mouse model.

Multipotent germline stem (mGS) cells have been established from neonatal mouse testes. We previously reported that undifferentiated mGS cells are phenotypically similar to embryonic stem cells and that fetal liver kinase 1 (Flk1)(+) mGS cells have a similar potential to differentiate into cardiomyocytes and endothelial cells compared with Flk1(+) embryonic stem cells. Here, we transplanted these Flk1(+) mGS cells into an ischemic heart failure mouse model to evaluate the improvement in cardiac function. Significant increase in left ventricular wall thickness of the infarct area, left ventricular ejection fraction and left ventricular maximum systolic velocity was observed 4weeks after when sorted Flk1(+) mGS cells were transplanted directly into the hearts of the acute ischemic model mice. Although the number of cardiomyocytes derived from Flk1(+) mGS cells were too small to account for the improvement in cardiac function but angiogenesis around ischemic area was enhanced in the Flk1(+) mGS cells transplanted group than the control group and senescence was also remarkably diminished in the early phase of ischemia according to ß-galactosidase staining assay. In conclusion, Flk1(+) mGS cell transplantation can improve the cardiac function of ischemic hearts by promoting angiogenesis and by delaying host cell death via senescence.

Successful treatment of pulmonary hypertension secondary to congenital extrahepatic portocaval shunts (Abernethy type 2) by living donor liver transplantation after surgical shunt ligation.

In this report, we describe a living donor liver transplantation (LDLT) in a patient (7-year-old boy) with Abernethy type 2 congenital extrahepatic portocaval shunts (CEPS). This patient underwent a surgical shunt ligation as the first treatment for pulmonary hypertension; pulmonary hypertension was improved and controlled successfully 4 years after the first operation. However, pulmonary hypertension recurred gradually because of multiple intrahepatic portosystemic shunts; therefore, LDLT was performed as a radical treatment of intrahepatic portosystemic shunts. His pulmonary arterial pressure was also controlled 22 months after LDLT, the postoperative continuous intravenous prostaglandin I(2) (PGI(2)) treatment could be withdrawn successfully. We suggest that clinicians carefully follow up the recurrent portosystemic shunt and cardiopulmonary disorders secondary to Abernethy type 2 CEPS.

The effects of cardioactive drugs on cardiomyocytes derived from human induced pluripotent stem cells.

Developing effective drug therapies for arrhythmic diseases is hampered by the fact that the same drug can work well in some individuals but not in others. Human induced pluripotent stem (iPS) cells have been vetted as useful tools for drug screening. However, cardioactive drugs have not been shown to have the same effects on iPS cell-derived human cardiomyocytes as on embryonic stem (ES) cell-derived cardiomyocytes or human cardiomyocytes in a clinical setting. Here we show that current cardioactive drugs affect the beating frequency and contractility of iPS cell-derived cardiomyocytes in much the same way as they do ES cell-derived cardiomyocytes, and the results were compatible with empirical results in the clinic. Thus, human iPS cells could become an attractive tool to investigate the effects of cardioactive drugs at the individual level and to screen for individually tailored drugs against cardiac arrhythmic diseases.

Flk1(+) cardiac stem/progenitor cells derived from embryonic stem cells improve cardiac function in a dilated cardiomyopathy mouse model.

OBJECTIVES: Flk1(+) cells derived from embryonic stem (ES) cells are known to differentiate into mesodermal lineages such as hematopoietic and endothelial cells. Here we demonstrate that they can develop into cardiomyocytes that support functional recovery in a dilated cardiomyopathy (DCM) C57/BL6 mouse model. METHODS: Flk1(+) and Flk1(-) cells were sorted at day 4 of differentiation, and cardiomyogenesis was assessed in vitro. Next, we transplanted these cells into the hearts of cardiomyopathy mice to assess improvement in cardiac function. RESULTS: Flk1(+) cells, but not Flk1(-) cells, isolated on day 4 after differentiation were efficiently converted into contractile cardiomyocytes. RT-PCR analysis and immunohistological assays demonstrated that contractile cells derived from Flk1(+) cells in vitro expressed mature cardiac markers on day 10 after differentiation. Transplantation of sorted Flk1(+) cells into DCM model mouse hearts improved cardiac function, as determined by echocardiography and cardiac catheterization. The in vivo differentiated Flk1(+) cells expressed cardiac markers and had gap junctions, as demonstrated by immunohistochemistry. Furthermore, these cells generated ventricular type action potentials similar to those of adult ventricle. CONCLUSION: These results indicate that Flk1 is a good marker for sorting cardiac stem/progenitor cells which can differentiate into mature cardiomyocytes both in vitro and in vivo.

Continuous infusion of lipo-prostaglandin E1 for Takayasu's arteritis with heart failure in an 11-month-old baby: a case report.

BACKGROUND: Takayasu's arteritis is extremely rare in children aged below 6 years. At the onset of Takayasu's arteritis in children, symptoms are varied but differ from those in adults. Corticosteroids are the mainstay of treatment for preventing irreversible vascular damage but there is no standard treatment for progressive vascular stenosis. CASE PRESENTATION: A Japanese 11-month-old baby boy presented with Takayasu's arteritis and heart failure, possibly due to afterload mismatch caused by high blood pressure. Computed tomography was performed and revealed thoracic and abdominal aortic aneurysms. It also revealed severe celiac artery stenosis and bilateral renal artery stenosis. Prednisolone was initiated as first-line therapy. The fever resolved, and C-reactive protein levels returned to normal. Although his general condition improved, deterioration of vascular lesions was evident. Celiac artery occlusion, severe right renal artery stenosis, and new superior mesenteric artery stenosis were observed. We decided to use a continuous infusion of lipo-prostaglandin E1 for prevention of branch stenosis of his abdominal aorta. The progression of vascular stenosis was stopped and our patient's cardiac function gradually improved. CONCLUSIONS: A differential diagnosis of heart failure with high blood pressure should be considered in babies. The progression of vascular stenosis may be suppressed by lipo-prostaglandin E1.

Starnes procedure for severe left atrioventricular valve regurgitation.

We present the case of a 19-day-old girl with incomplete atrioventricular septal defect, muscular ventricular septal defect, and severe left atrioventricular valve regurgitation. We attempted biventricular repair with left atrioventricular valve repair; however, we could not control the regurgitation. Moreover, the commercially available prosthetic valve was too large to implant. Thus we switched intraoperatively to a univentricular repair. We successfully performed patch closure of the left atrioventricular valve (Starnes procedure), Damus-Kaye-Stansel anastomosis, and a systemic-to-pulmonary artery shunt.

Identification of cardiac stem cells with FLK1, CD31, and VE-cadherin expression during embryonic stem cell differentiation.

We evaluated the expression of the FLK1, one of the lateral mesoderm early markers where cardiogenesis occurs, to characterize and isolate cardiac stem/progenitor cells from ES cells. Dissociated cells from embryoid bodies (EBs) on day 3, 4, or 5 were collected into two subpopulations with or without FLK1 expression and coculture on OP9 stromal cells was continued to examine whether contracting colonies came out or not. FLK1+ cells from EBs at days 3 and 4 formed spontaneous contracting colonies more efficiently than FLK1- cells on the same days, but not at day 5. Most contracting cardiac colonies derived from FLK1+cells mainly on day 4 were detected on endothelial cells along with hematopoietic cells. Further characterization of cells with these capabilities into three lineages revealed the FLK1+ CD31-VE-cadherin-phenotype. Our findings indicate that FLK1+cells, especially FLK1+ CD31-VE-cadherin-cells, could act as cardiohemangioblasts to form cardiac cells as well as endothelial cells and hematopoietic cells.

Exon skipping causes atypical phenotypes associated with a loss-of-function mutation in FLNA by restoring its protein function.

Loss-of-function mutations in filamin A (FLNA) cause an X-linked dominant disorder with multiple organ involvement. Affected females present with periventricular nodular heterotopia (PVNH), cardiovascular complications, thrombocytopenia and Ehlers-Danlos syndrome. These mutations are typically lethal to males, and rare male survivors suffer from failure to thrive, PVNH, and severe cardiovascular and gastrointestinal complications. Here we report two surviving male siblings with a loss-of-function mutation in FLNA. They presented with multiple complications, including valvulopathy, intestinal malrotation and chronic intestinal pseudo-obstruction (CIPO). However, these siblings had atypical clinical courses, such as a lack of PVNH and a spontaneous improvement of CIPO. Trio-based whole-exome sequencing revealed a 4-bp deletion in exon 40 that was predicted to cause a lethal premature protein truncation. However, molecular investigations revealed that the mutation induced in-frame skipping of the mutated exon, which led to the translation of a mutant FLNA missing an internal region of 41 amino acids. Functional analyses of the mutant protein suggested that its binding affinity to integrin, as well as its capacity to induce focal adhesions, were comparable to those of the wild-type protein. These results suggested that exon skipping of FLNA partially restored its protein function, which could contribute to amelioration of the siblings' clinical courses. This study expands the diversity of the phenotypes associated with loss-of-function mutations in FLNA.

[Postoperative complete atrioventricular block induced by carbamazepine in a patient with congenital heart disease].

We report here a boy with epilepsy and congenital heart defect, complicated postoperatively by complete atrioventricular (A-V) block caused by an adverse effect of carbamazepine (CBZ). He had been taking CBZ for 7 years to treat complex partial seizures. He also had endocardial cushion defect and first-degree A-V block, and underwent cardiac surgery at the age of 17 years. The postoperative course was unremarkable except transient complete left bundle branch block occuring one day after the surgery. Oral CBZ (400 mg per day) was continued. Five days after the surgery, bradycardia (20 beats per minute) suddenly developed, and electrocardiography (ECG) showed complete A-V block. Pervenous pacing was begun, and the heart rate gradually recovered. CBZ was discontinued on the suspicion that it caused the arrhythmia, although its serum level was estimated to be within the therapeutic range (4 to 5 microg/ml). He underwent pervenous pacing for 12 days. He was discharged 27 days after the surgery, when ECG returned to first-degree A-V block. In this case, the cardiac conduction system was affected by an adverse effect of CBZ, in combination with the preoperative first-degree A-V block and the effects of cardiac surgery, resulting in complete A-V block. Although reports of similar cases are scarce, caution should be made in prescribing CBZ to patients who either have cardiac conduction abnormalities or undergo cardiac surgery.