Apoptosis of cardiomyocytes in children with right ventricular pressure overload with and without hypoxemia.

BACKGROUND: Cardiomyocyte apoptosis has been implicated in ventricular remodeling and initiation of cardiac failure. We sought to determine the severity of right ventricular (RV) cardiomyocyte apoptosis in cyanotic and acyanotic children with RV pressure overload. METHODS: Fourteen patients, seven with tetralogy of Fallot (group I) and seven with pulmonary stenosis and ventricular septal defect (group II), undergoing open-heart surgery were studied. Right ventricular biopsies were examined for cardiomyocyte apoptosis by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling. The magnitude of cardiomyocyte apoptosis was related to preoperative oxygen saturation and postoperative inotrope use and hospital stay. RESULTS: Compared with group I patients, group II patients were significantly older at operation (p = 0.002) and had a larger body size (p < 0.01) and higher preoperative oxygen saturation (p = 0.01). The prevalence of cardiomyocyte apoptosis in both group I and II patients as a whole was 0.24 ± 0.29% (range, 0% to 1.10%). The prevalence was similar between group I (median 0.30%, range 0% to 1.10%) and group II (median 0.20, range 0% to 0.40%, p = 0.65). The prevalence of cardiomyocyte apoptosis correlated positively with preoperative oxygen saturation on room air (r = -0.69, p < 0.005) and postoperative inotrope score (r = 0.67, p = 0.001). A higher postoperative inotrope score (r = 0.68, p = 0.001) was associated with a significant longer duration of postoperative stay in the hospital. CONCLUSIONS: The prevalence of cardiomyocyte apoptosis in the pressure-overloaded right ventricle is related to the severity of hypoxia and may have an impact on postoperative course in terms of early postoperative use of inotropes and duration of hospital stay.

Functional transient receptor potential canonical type 1 channels in human atrial myocytes.

Transient receptor potential (TRP) channels are not well understood in human atrium, and the present study was therefore designed to investigate whether TRPC channels would mediate the nonselective cation current reported previously and are involved in the formation of store-operated Ca(2+) entry (SOCE) channels in human atrial myocytes using approaches of whole-cell patch voltage-clamp, RT-PCR, Western blotting, co-immunoprecipitation, and confocal scanning approaches, etc. We found that a nonselective cation current was recorded under K(+)-free conditions in human atrial myocytes, and the current was inhibited by the TRP channel blocker La(3+). Thapsigargin enhanced the current, and its effect was suppressed by La(3+) and prevented by pipette inclusion of anti-TRPC1 antibody. Endothlin-1 and angiotensin II enhanced the current that could be inhibited by La(3+). Gene and protein expression of TRPC1 channels were abundant in human atria. In addition, mRNA and protein of STIM1 and Orai1, components of SOCE channels, were abundantly expressed in human atria. Co-immunoprecipitation analysis demonstrated an interaction of TRPC1 with STIM1 and/or Orai1. Ca(2+) signaling mediated by SOCE channels was detected by a confocal microscopy technique. These results demonstrate the novel evidence that TRPC1 channels not only mediate the nonselective cation current, but also form SOCE channels in human atria as a component. TRPC1 channels can be activated by endothelin-1 or angiotensin II, which may be involved in the atrial electrical remodeling in patients with atrial fibrillation.

Evidence for functional expression of TRPM7 channels in human atrial myocytes.

Transient receptor potential melastatin-7 (TRPM7) channels have been recently reported in human atrial fibroblasts and are believed to mediate fibrogenesis in human atrial fibrillation. The present study investigates whether TRPM7 channels are expressed in human atrial myocytes using whole-cell patch voltage-clamp, RT-PCR and Western blotting analysis. It was found that a gradually activated TRPM7-like current was recorded with a K(+)- and Mg(2+)-free pipette solution in human atrial myocytes. The current was enhanced by removing extracellular Ca(2+) and Mg(2+), and the current increase could be inhibited by Ni(2+) or Ba(2+). The TRPM7-like current was potentiated by acidic pH and inhibited by La(3+) and 2-aminoethoxydiphenyl borate. In addition, Ca(2+)-activated TRPM4-like current was recorded in human atrial myocytes with the addition of the Ca(2+) ionophore A23187 in bath solution. RT-PCR and Western immunoblot analysis revealed that in addition to TRPM4, TRPM7 channel current, mRNA and protein expression were evident in human atrial myocytes. Interestingly, TRPM7 channel protein, but not TRPM4 channel protein, was significantly increased in human atrial specimens from the patients with atrial fibrillation. Our results demonstrate for the first time that functional TRPM7 channels are present in human atrial myocytes, and the channel expression is upregulated in the atria with atrial fibrillation.

Trends in contemporary advanced heart failure management: an in-depth review over 30 years of heart transplant service in Hong Kong.

Background: The year 2022 marks the 30th anniversary of heart transplant service in Hong Kong (HK). In this study, we describe prevailing trends and outcomes of advanced heart failure (AHF), including heart transplantations (HTx), in HK over the past 30 years. Methods: Trends in heart failure prevalence in HK from 1993 to 2021 were analyzed based on data from the Hospital Authority Clinical Data and Reporting System. All AHF patients referred for HTx consideration between 1992 and 2021 were reviewed. The bridge-to-transplant (BTT) utilization of short-term mechanical circulatory support (ST-MCS) devices, including venoarterial extracorporeal membrane oxygenation (VA-ECMO) and durable left ventricular assist devices (LVADs), from 2010 to 2021 was reviewed. Results: Overall, 237 heart transplants were performed in HK, with 10-year posttransplant and median survival of 68.1% and 18.7 years, respectively. An increase in AHF clinic referrals was correlated with increasing heart failure prevalence (R2=0.635, P<0.001). In total, 146 referrals were made for ST-MCS, and an observed increase in ST-MCS referrals was correlated with increasing VA-ECMO utilization (R2=0.849, P<0.001). Among 62 patients accepted for AHF therapy, those with durable LVAD implementation had better 1-year survival (71.5%) than those receiving an extracorporeal CentriMag (Levitronix) device as BTT (40%, P=0.008). In total, 143 LVADs were implanted, with 130 as BTT or bridge-to-candidacy (BTC) methods. The survival rate among the 130 BTT/BTC LVAD patients resembled that of HTx recipients (73.8% vs. 69.8% at 9 years, P=0.296). Conclusions: The burden of AHF management has increased and gained complexity over the past 30 years in Hong Kong.

A novel KIF5B-ALK variant in nonsmall cell lung cancer.

BACKGROUND: The anaplastic lymphoma kinase (ALK) gene is involved frequently in chromosomal translocations, resulting in fusion genes with different partners found in various lymphoproliferative conditions. It was recently reported in nonsmall cell lung cancer (NSCLC) that the fusion protein encoded by echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK) fusion gene conferred oncogenic properties. The objective of the current study was to identify other possible ALK fusion genes in NSCLC. METHODS: Immunohistochemical analysis was used to screen for aberrant ALK expression in primary NSCLC. The authors used 5' rapid amplification of complementary DNA ends to screen for potential, novel 5' fusion partners of ALK other than EML4-ALK. Reverse transcriptase-polymerase chain reaction and fluorescence in situ hybridization analyses were used to confirm the identity of 5' fusion partners. The genomic breakpoint was verified using genomic sequencing. Overexpression of the novel ALK fusion gene and variants 3a and 3b of EML4-ALK was performed to assess downstream signaling and functional effects. RESULTS: The authors identified a novel gene resulting from the fusion of kinesin family member 5B (KIF5B) exon 15 to ALK exon 20 in a primary lung adenocarcinoma. Western blot analysis of clinical tumor tissues revealed the expression of a protein whose size correlated with that of the predicted KIF5B-ALK. Overexpression of KIF5B-ALK in mammalian cells led to the activation of signal transducer and activator of transcription 3 and protein kinase B and to enhanced cell proliferation, migration, and invasion. CONCLUSIONS: The discovery of the novel KIF5B-ALK variant further consolidated the role of aberrant ALK signaling in lung carcinogenesis.

Acacetin, a natural flavone, selectively inhibits human atrial repolarization potassium currents and prevents atrial fibrillation in dogs.

BACKGROUND: The development of atrium-selective antiarrhythmic agents is a current strategy for inhibiting atrial fibrillation (AF). The present study investigated whether the natural flavone acacetin from the traditional Chinese medicine Xuelianhua would be an atrium-selective anti-AF agent. METHODS AND RESULTS: The effects of acacetin on human atrial ultrarapid delayed rectifier K(+) current (I(Kur)) and other cardiac ionic currents were studied with a whole-cell patch technique. Acacetin suppressed I(Kur) and the transient outward K(+) current (IC(50) 3.2 and 9.2 mumol/L, respectively) and prolonged action potential duration in human atrial myocytes. The compound blocked the acetylcholine-activated K(+) current; however, it had no effect on the Na(+) current, L-type Ca(2+) current, or inward-rectifier K(+) current in guinea pig cardiac myocytes. Although acacetin caused a weak reduction in the hERG and hKCNQ1/hKCNE1 channels stably expressed in HEK 293 cells, it did not prolong the corrected QT interval in rabbit hearts. In anesthetized dogs, acacetin (5 mg/kg) prolonged the atrial effective refractory period in both the right and left atria 1 to 4 hours after intraduodenal administration without prolongation of the corrected QT interval, whereas sotalol at 5 mg/kg prolonged both the atrial effective refractory period and the corrected QT interval. Acacetin prevented AF induction at doses of 2.5 mg/kg (50%), 5 mg/kg (85.7%), and 10 mg/kg (85.7%). Sotalol 5 mg/kg also prevented AF induction (60%). CONCLUSIONS: The present study demonstrates that the natural compound acacetin is an atrium-selective agent that prolongs the atrial effective refractory period without prolonging the corrected QT interval and effectively prevents AF in anesthetized dogs after intraduodenal administration. These results indicate that oral acacetin is a promising atrium-selective agent for the treatment of AF.

Lung transplantation in Hong Kong: 12 years of experience.

BACKGROUND AND OBJECTIVE: A lung transplant programme was launched in August 1994 at Grantham Hospital in Hong Kong with the first single-lung transplant performed in July 1995. A retrospective study was undertaken of all patients who had undergone lung transplantation and their outcomes analysed. METHODS: Data were collected from hospital and outpatient records. RESULTS: There were 12 transplants (two single-lung and 10 double-lung) performed in the 12 years to December 2006. No postoperative or early mortality was observed. In addition to the usual complications there were two cases of early pulmonary tuberculosis and one rare case of delayed fungal sternotomy infection. The 1-year, 3-year and 5-year survival rates were 100%, 100% and 76.2%, respectively. All fatalities were related to the consequences of chronic rejection or its treatment. CONCLUSIONS: Despite the limited experience and the small case volume, the survival of patients was good and comparable with international experience.

Improved leg wound healing with endoscopic saphenous vein harvest in coronary artery bypass graft surgery: a prospective randomized study in Asian population.

OBJECTIVE: Conventional open saphenous vein harvest (OVH) for coronary artery bypass graft surgery is often associated with significant pain and morbidity. This study aims to determine whether endoscopic saphenous vein harvest (EVH) reduces leg wound morbidity and improves patient satisfaction as compared to OVH in Asian population. METHODS: Between March 2005 and June 2006, 120 patients who underwent isolated CABG were prospectively randomized into EVH (n = 60) and OVH (n = 60) groups. VirtuoSaph (Terumo Cardiovascular Corp., Ann Arbor, MI, USA) harvesting system was used for EVH. We analyzed leg wound complications (ASEPSIS score), postoperative pain, satisfaction, and clinical outcomes. Fisher's exact test and Mann-Whitney U test were used for categorical and continuous variables analysis respectively. RESULTS: Six patients in the EVH group required conversion to open technique. Both groups had matched demographic characteristics and risk factors. Mean numbers of grafts performed were 3.2 +/- 0.6 (EVH n = 54) and 3.0 +/- 0.7 (OVH n = 60) (p = 0.03). ASEPSIS scores at postoperation days three, seven, and 21 were significantly lower in the EVH group than the OVH group (p = 0.02, p = 0.002 and p = 0.01, respectively). Wound pain scores at postoperative days three, seven, and 21 were significantly lower in the EVH group (p = 0.000, p = 0.001 and p = 0.000 respectively). Wound numbness was found in 5.7% of the EVH group and 33.3% of the OVH group patients (p = 0.01). [Six patients required conversion to open technique.] There was one hospital mortality (OVH group) and major postoperative complications were not significantly different between the groups. CONCLUSION: EVH system is a safe and effective alternative to OVH with better wound healing, reduced postoperative pain, and wound numbness. However, the higher conversion rate to OVH in Asian patients requires further evaluation.

Pulmonary alveolar proteinosis in extremis: the case for aggressive whole lung lavage with extracorporeal membrane oxygenation support.

Pulmonary alveolar proteinosis (PAP) is a rare disorder in which lipoproteinaceous material is deposited in the alveoli, compromising gaseous exchange. We report the case of a 29-year-old female patient presenting with the most extreme case of PAP yet reported. She successfully managed by aggressive bilateral whole lung lavage (WLL) in a single sitting using extracorporeal membrane oxygenation (ECMO) support. Despite critical hypercarbia and ventilator-dependence for 12 days before lavage, the patient experienced rapid recovery of pulmonary function after WLL and ECMO could be discontinued on-table. Aggressive WLL with ECMO support can be safe and effective even in the most severe cases of PAP.

Biatrial pacing to prevent atrial fibrillation after coronary artery bypass.

Between October 1999 and December 2000, 52 patients (37 male) undergoing coronary artery bypass surgery were selected for overdrive biatrial pacing to determine its effectiveness in reducing atrial fibrillation. A pacing wire was attached to the right atrial appendage and another to the roof of the left atrium behind the aorta. The atria were paced continuously in AAI mode at a rate of 90 pulses per minute or 10 pulses above the underlying rate (maximum rate < 140/min) for 3 days. The endpoint was the onset of atrial fibrillation during hospital stay. Results were compared with those of a control group of 52 matched patients. There were no significant differences in the occurrence of atrial fibrillation (30% in the paced group vs. 25% in the control group), morbidity, or length of hospital stay. Continuous biatrial pacing after coronary bypass surgery was safe and well tolerated, however, it did not prevent or lower the incidence of atrial fibrillation.

Post-infarction ventricular septal defect: surgical outcomes in the last decade.

BACKGROUND: Post-infarction ventricular septal defects require surgical closure. Only a few studies have been conducted in Asian populations. This study reports the current outcomes and determinants affecting survival. METHODS: Between January 1995 and January 2012, 40 patients underwent surgery for post-infarction ventricular septal defect. We analyzed demographics, clinical, angiographic, and echocardiographic parameters, operative data, postoperative morbidity, and survival. Mean follow-up was 5.2 ± 5.3 years. Univariate and multivariate analyses were used to determine the factors affecting 30-day mortality and long-term survival. RESULTS: There was no intraoperative death. Our 30-day mortality was 20%. Single-vessel disease was found on coronary angiography in 63% of patients. Eight patients had concomitant coronary artery bypass grafting. Overall survival at 1, 5, and 10 years was 68%, 55%, and 42%, respectively. Event-free survival from subsequent angina, myocardial infarction, congestive heart failure, or percutaneous interventions at 1, 5, and 10 years was 66%, 43%, and 25%, respectively. Preoperative oliguria and postoperative sepsis were independent predictors of 30-days mortality on multivariate analysis (p = 0.02). Preoperative left ventricular function was associated with long-term survival (p = 0.048). CONCLUSION: We had good results of current postinfarction ventricular septal defect repair. Selected patients had concomitant coronary artery bypass grafting. Preoperative oliguria and postoperative sepsis were independent predictors of 30-day mortality, while left ventricular function was related to long-term survival.

Improvising hepatic venous outflow and inferior vena cava reconstruction for combined heart and liver and sequential liver transplantations.

Liver transplantation is a standard treatment for patients with familial amyloidotic polyneuropathy (FAP) with disease progression. Given the multiorgan involvement by amyloidosis, the heart is often involved. When poor cardiac function becomes prohibitive to liver transplantation, a combined heart-liver transplantation (CHLT) is the only realistic treatment. This article records a CHLT for a patient with FAP whose removed liver was immediately transplanted as an amyloidotic hepatic allograft (AHA) to a patient having hepatocellular carcinoma and cirrhosis in a sequential liver transplantation. In the CHLT, the heart and liver are donated by a deceased donor. The newly implanted heart did not tolerate cross clamping of the inferior vena cava (IVC), so a side-to-side anastomosis was performed to connect the IVC and that of the liver graft. Therefore, the AHA was devoid of an IVC. The infrarenal cava procured from the deceased donor was used for reconstruction of the AHA to match a whole graft used in routine deceased-donor liver transplantation. Venoplasty was performed using the graft right hepatic vein and the middle and left hepatic vein stump to form a single cuff. The reconstructed AHA was implanted to the recipient conveniently like a usual whole graft.

Modulation of human cardiac transient outward potassium current by EGFR tyrosine kinase and Src-family kinases.

AIMS: The human cardiac transient outward K(+) current I(to) (encoded by Kv4.3 or KCND3) plays an important role in phase 1 rapid repolarization of cardiac action potentials in the heart. However, modulation of I(to) by intracellular signal transduction is not fully understood. The present study was therefore designed to determine whether/how human atrial I(to) and hKv4.3 channels stably expressed in HEK 293 cells are regulated by protein tyrosine kinases (PTKs). METHODS AND RESULTS: Whole-cell patch voltage-clamp, immunoprecipitation, western blotting, and site-directed mutagenesis approaches were employed in the present study. We found that human atrial I(to) was inhibited by the broad-spectrum PTK inhibitor genistein, the selective epidermal growth factor receptor (EGFR) kinase inhibitor AG556, and the Src-family kinases inhibitor PP2. The inhibitory effect was countered by the protein tyrosine phosphatase inhibitor orthovanadate. In HEK 293 cells stably expressing human KCND3, genistein, AG556, and PP2 significantly reduced the hKv4.3 current, and the reduction was antagonized by orthovanadate. Interestingly, orthovanadate also reversed the reduced tyrosine phosphorylation level of hKv4.3 channels by genistein, AG556, or PP2. Mutagenesis revealed that the hKv4.3 mutant Y136F lost the inhibitory response to AG556, while Y108F lost response to PP2. The double-mutant Y108F-Y136F hKv4.3 channels showed no response to either AG556 or PP2. CONCLUSION: Our results demonstrate that human atrial I(to) and cloned hKv4.3 channels are modulated by EGFR kinase via phosphorylation of the Y136 residue and by Src-family kinases via phosphorylation of the Y108 residue; tyrosine phosphorylation of the channel may be involved in regulating cardiac electrophysiology.

Late tricuspid surgery: predicting outcome with computed tomography.

Tricuspid regurgitation can progressively worsen years after left-sided heart valve surgery, requiring surgical intervention for which the prognostic factors are unclear. This study aimed to assess the prediction of surgical outcome using right ventricular function obtained from computed tomography. We prospectively enrolled 24 patients who underwent isolated tricuspid repair or replacement from 2005 to 2008. Right ventricular computed tomography was carried out before surgery. The primary endpoint was survival with symptomatic improvement after one year. Twelve patients survived with improvement of at least one New York Heart Association functional class, and 12 died or had no symptomatic improvement. All baseline characteristics, echocardiogram data, and surgical details were similar in both groups. Right ventricular computed tomography parameters including end-systolic volume, indexed end-systolic volume, end-diastolic volume, and indexed end-diastolic volume were significantly different between the two groups. We concluded that right ventricular function assessed by computed tomography can predict the surgical outcome in patients undergoing surgery for isolated late tricuspid regurgitation.

Management of symptomatic congenital tracheal stenosis in neonates and infants by slide tracheoplasty: a 7-year single institution experience.

OBJECTIVE: Congenital tracheal stenosis (CTS) is rare. When it presents early in life, its management can be challenging. Of the surgical techniques that have been devised to correct long-segment CTS, slide tracheoplasty (ST) appears to be superior. We present our 7-year-experience of ST for the treatment of symptomatic CTS in neonates and infants. METHODS: The hospital records of all 14 neonates and infants who underwent ST between 2001 and 2008 at our hospital were retrieved. Patient characteristics, trachea morphology, co-existing anomalies, operative procedures, techniques, outcomes and clinical courses were reviewed. RESULTS: Patients underwent ST at age 4 days to 22 months (median: 2.4 months). Five (36%) required intermittent ventilator support prior to surgery. All ST was done under cardiopulmonary bypass. The associated cardiovascular anomalies in 10 infants (71%) were also corrected at the same operation. All survived the initial surgical procedures. The in-hospital mortality for the group was 14.3%. The median periods of postoperative intensive care unit and hospital stay of the 12 children, who were successfully extubated within 7 postoperative days, were 9 days (range: 6-28 days) and 28 days (range: 14-375 days), respectively. Follow-up of all 12 midterm survivors was complete, ranging from 5 months to 5.6 years (median: 40 months). A total of four patients had been found to have tracheobronchial malacia postoperatively and were managed with stenting. Of the remaining 10 survivors who had no residual or recurrent airway problems, and no cardiovascular residuum or sequela, two had gross developmental delay. CONCLUSIONS: In the management of symptomatic infants with CTS, our limited experience suggests that meticulously performed ST together with vigilant pre- and postoperative care can provide satisfactory short and midterm solution to the airway problem. Some incidental residual clinical problems appear to be unavoidable.

Positron-emission tomography for lung cancer in a tuberculosis-endemic region.

A potential limitation of integrated positron-emission tomography and computed tomography in non-small-cell lung cancer may be false-positive results due to granulomatous disease. This retrospective study examined the accuracy of this imaging modality for mediastinal nodal staging of non-small-cell lung cancer in Hong Kong where tuberculosis remains endemic. There were 249 lymph node stations evaluated in 107 patients, of whom 38 (36%) had active tuberculosis or evidence of previous tuberculosis. Imaging results were compared with histological findings. The sensitivity, specificity, and accuracy of integrated imaging for mediastinal nodal staging were 52%, 86%, and 80%, respectively; the overall positive-predictive value for mediastinal nodal metastasis was 46%, and the overall negative-predictive value was 89%. The positive-predictive value for mediastinal nodal metastasis was 39% in patients with tuberculosis and 50% in controls; the negative-predictive value was high in both groups (92% and 87%). The likelihood ratio for true positives was 6.47 in patients with tuberculosis vs. 10.97 in controls. This suggests that the reliability of positron-emission/computed tomography may be substantially poorer in patients with tuberculosis. Histological confirmation should be considered mandatory in patients with suspected metastasis on integrated imaging.

Non-small cell lung cancer cells expressing CD44 are enriched for stem cell-like properties.

BACKGROUND: The cancer stem cell theory hypothesizes that cancers are perpetuated by cancer stem cells (CSC) or tumor initiating cells (TIC) possessing self-renewal and other stem cell-like properties while differentiated non-stem/initiating cells have a finite life span. To investigate whether the hypothesis is applicable to lung cancer, identification of lung CSC and demonstration of these capacities is essential. METHODOLOGY/PRINCIPAL FINDING: The expression profiles of five stem cell markers (CD34, CD44, CD133, BMI1 and OCT4) were screened by flow cytometry in 10 lung cancer cell lines. CD44 was further investigated by testing for in vitro and in vivo tumorigenecity. Formation of spheroid bodies and in vivo tumor initiation ability were demonstrated in CD44(+) cells of 4 cell lines. Serial in vivo tumor transplantability in nude mice was demonstrated using H1299 cell line. The primary xenografts initiated from CD44(+) cells consisted of mixed CD44(+) and CD44(-) cells in similar ratio as the parental H1299 cell line, supporting in vivo differentiation. Semi-quantitative Real-Time PCR (RT-PCR) showed that both freshly sorted CD44(+) and CD44(+) cells derived from CD44(+)-initiated tumors expressed the pluripotency genes OCT4/POU5F1, NANOG, SOX2. These stemness markers were not expressed by CD44(-) cells. Furthermore, freshly sorted CD44(+) cells were more resistant to cisplatin treatment with lower apoptosis levels than CD44(-) cells. Immunohistochemical analysis of 141 resected non-small cell lung cancers showed tumor cell expression of CD44 in 50.4% of tumors while no CD34, and CD133 expression was observed in tumor cells. CD44 expression was associated with squamous cell carcinoma but unexpectedly, a longer survival was observed in CD44-expressing adenocarcinomas. CONCLUSION/SIGNIFICANCE: Overall, our results demonstrated that stem cell-like properties are enriched in CD44-expressing subpopulations of some lung cancer cell lines. Further investigation is required to clarify the role of CD44 in tumor cell renewal and cancer propagation in the in vivo environment.

Omega-3 polyunsaturated fatty acids inhibit transient outward and ultra-rapid delayed rectifier K+currents and Na+current in human atrial myocytes.

AIMS: The omega-3 (n-3) polyunsaturated fatty acids (omega-3 PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish oil were recently reported to have an anti-atrial fibrillation effect in humans; however, the ionic mechanisms of this effect are not fully understood. The present study was designed to determine the effects of EPA and DHA on transient outward and ultra-rapid delayed rectifier potassium currents (I(to) and I(Kur)) and the voltage-gated sodium current (I(Na)) in human atrial myocytes. METHODS AND RESULTS: A whole-cell patch voltage clamp technique was employed to record I(to) and I(Kur), and I(Na) in human atrial myocytes. It was found that EPA and DHA inhibited I(to) in a concentration-dependent manner (IC(50): 6.2 microM for EPA; 4.1 microM for DHA) and positively shifted voltage-dependent activation of the current. In addition, I(Kur) was suppressed by 1-50 microM EPA (IC(50): 17.5 microM) and DHA (IC(50): 4.3 microM). Moreover, EPA and DHA reduced I(Na) in human atrial myocytes in a concentration-dependent manner (IC(50): 10.8 microM for EPA; 41.2 microM for DHA) and negatively shifted the potential of I(Na) availability. The I(Na) block by EPA or DHA was use-independent. CONCLUSION: The present study demonstrates for the first time that EPA and DHA inhibit human atrial I(to), I(Kur), and I(Na) in a concentration-dependent manner; these effects may contribute, at least in part, to the anti-atrial fibrillation of omega-3 PUFAs in humans.