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.

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.

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.

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.

Multiple pulmonary metastases from benign pleomorphic adenoma.

Metastasizing pleomorphic adenoma is a rare condition of metastasis from a histologically benign salivary gland tumor. We report a case of metastasizing pleomorphic adenoma presenting with multiple bilateral lung metastases, and discuss the clinical aspects of this disease.

Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features.

PURPOSE: This study evaluated the mutational profile of epidermal growth factor receptor (EGFR) and KRAS in non-small cell lung cancers in Hong Kong and determined their relation with smoking history and other clinicopathologic features. EXPERIMENTAL DESIGN: Mutational profile of exons 18 to 21 of EGFR and codons 12, 13, and 61 of KRAS were determined in 215 adenocarcinomas, 15 squamous cell (SCC), and 11 EBV-associated lymphoepithelioma-like carcinomas (LELC). RESULTS: EGFR mutations were prevalent in adenocarcinomas (115 of 215), uncommon in LELC (1 of 11), and not found in SCC (P < 0.001). Among adenocarcinomas, mutations were associated with nonsmokers (83 of 111; P < 0.001), female gender (87 of 131; P < 0.001), and well-differentiated (55 of 86) compared with poorly differentiated (11 of 41) tumors (P < 0.001). Decreasing mutation rates with increasing direct tobacco exposure was observed, with 74.8% (83 of 111) in nonsmokers, 61.1% (11 of 18) in passive, 35.7% (10 of 28) in previous, and 19.0% (11 of 58) in current smokers. There were 53% amino acid substitutions, 43% in-frame deletions, and 4% insertions. Complex patterns with 13% double mutations, including five novel substitutions, were observed. For KRAS, mutations occurred in adenocarcinoma only (21 of 215) and were associated with smokers (11 of 58; P = 0.003), men (14 of 84; P = 0.009) and poorly differentiated (7 of 41) compared with well-differentiated (4 of 86) tumors (P = 0.037). EGFR and KRAS mutations occurred in mutually exclusive tumors. Regression analysis showed smoking history was the significant determinant for both mutations, whereas gender was a confounding factor. CONCLUSION: This study shows EGFR mutations are prevalent in lung adenocarcinoma and suggests that it plays an increasing oncogenic role with decreasing direct tobacco damage.

Effects of diltiazem and nifedipine on transient outward and ultra-rapid delayed rectifier potassium currents in human atrial myocytes.

1. It is unknown whether the widely used L-type Ca(2+) channel antagonists diltiazem and nifedipine would block the repolarization K(+) currents, transient outward current (I(to1)) and ultra-rapid delayed rectifier K(+) current (I(Kur)), in human atrium. The present study was to determine the effects of diltiazem and nifedipine on I(to1) and I(Kur) in human atrial myocytes with whole-cell patch-clamp technique. 2. It was found that diltiazem substantially inhibited I(to1) in a concentration-dependent manner, with an IC(50) of 29.2+/-2.4 microM, and nifedipine showed a similar effect (IC(50)=26.8+/-2.1 muM). The two drugs had no effect on voltage-dependent kinetics of the current; however, they accelerated I(to1) inactivation significantly, suggesting an open channel block. 3. In addition, diltiazem and nifedipine suppressed I(Kur) in a concentration-dependent manner (at +50 mV, IC(50)=11.2+/-0.9 and 8.2+/-0.8 microM, respectively). These results indicate that the Ca(2+) channel blockers diltiazem and nifedipine substantially inhibit I(to1) and I(Kur) in human atrial myocytes.

Differential effects of tyrosine kinase inhibitors on volume-sensitive chloride current in human atrial myocytes: evidence for dual regulation by Src and EGFR kinases.

To determine whether protein tyrosine kinase (PTK) modulates volume-sensitive chloride current (I(Cl.vol)) in human atrial myocytes and to identify the PTKs involved, we studied the effects of broad-spectrum and selective PTK inhibitors and the protein tyrosine phosphatase (PTP) inhibitor orthovanadate (VO(4)(-3)). I(Cl.vol) evoked by hyposmotic bath solution (0.6-times isosmotic, 0.6T) was enhanced by genistein, a broad-spectrum PTK inhibitor, in a concentration-dependent manner (EC(50) = 22.4 microM); 100 microM genistein stimulated I(Cl.vol) by 122.4 +/- 10.6%. The genistein-stimulated current was inhibited by DIDS (4,4'-diisothiocyanostilbene-2,2'-disulfonic acid, 150 microM) and tamoxifen (20 microM), blockers of I(Cl.vol). Moreover, the current augmented by genistein was volume dependent; it was abolished by hyperosmotic shrinkage in 1.4T, and genistein did not activate Cl(-) current in 1T. In contrast to the stimulatory effects of genistein, 100 microM tyrphostin A23 (AG 18) and A25 (AG 82) inhibited I(Cl.vol) by 38.2 +/- 4.9% and 40.9 +/- 3.4%, respectively. The inactive analogs, daidzein and tyrphostin A63 (AG 43), did not alter I(Cl.vol). In addition, the PTP inhibitor VO(4)(-3) (1 mM) reduced I(Cl.vol) by 53.5 +/- 4.5% (IC(50) = 249.6 microM). Pretreatment with VO(4)(-3) antagonized genistein-induced augmentation and A23- or A25-induced suppression of I(Cl.vol). Furthermore, the selective Src-family PTK inhibitor PP2 (5 microM) stimulated I(Cl.vol), mimicking genistein, whereas the selective EGFR (ErbB-1) kinase inhibitor tyrphostin B56 (AG 556, 25 microM) reduced I(Cl.vol), mimicking A23 and A25. The effects of both PP2 and B56 also were substantially antagonized by pretreatment with VO(4)(-3). The results suggest that I(Cl.vol) is regulated in part by the balance between PTK and PTP activity. Regulation is complex, however. Src and EGFR kinases, distinct soluble and receptor-mediated PTK families, have opposing effects on I(Cl.vol), and multiple target proteins are likely to be involved.

Inhibition of ultra-rapid delayed rectifier K+ current by verapamil in human atrial myocytes.

Verapamil is a widely used Ca(2+) channel antagonist in the treatment of cardiovascular disorders including atrial arrhythmias. However, it is unknown whether the drug would inhibit the repolarization currents transient outward K(+) current (I(to1)) and ultra-rapid delayed rectifier K(+) current (I(Kur)) in human atrium. With whole-cell patch configuration, we evaluated effects of verapamil on I(to1) and I(Kur) in isolated human atrial myocytes. It was found that verapamil did not decrease I(to1) at 1-50 microM. However, verapamil reversibly inhibited I(Kur) in a concentration-dependent manner (IC(50) = 3.2 microM). At test potential of +50 mV, 5 microM verapamil decreased I(Kur) by 61.3 +/- 7.5%. Verapamil significantly accelerated inactivation of I(Kur), suggesting an open channel block mechanism. The results indicate that verapamil significantly blocks the repolarization K(+) current I(Kur), but not I(to1), in human atrial atrium, which may account at least in part for the atrial effect of the drug.

Effects of chromanol 293B on transient outward and ultra-rapid delayed rectifier potassium currents in human atrial myocytes.

It is unclear whether chromanol 293B, a selective inhibitor of slow component of delayed rectifier K(+) current (I(Ks)), may affect other K(+) currents in human atrium. With whole-cell patch configuration, we evaluated effects of 293B on transient outward K(+) current (I(to1)) and ultra-rapid delayed rectifier K(+) current (I(Kur)) in isolated human atrial myocytes. It was found that 293B inhibited I(to1) and I(Kur) in a concentration-dependent manner. At 10 microM 293B suppressed I(to1) to 3.4 +/- 0.4 from 5.1 +/- 0.3 pA/pF (P < 0.01), and I(Kur) to 1.5 +/- 0.2 from 2.1 +/- 0.3 pA/pF (P < 0.01) at +50 mV. The inhibition of I(to1) and I(Kur) was independent of depolarizing voltage, and the concentration of 50% inhibition was 31.2 microM for I(to1), and 30.9 microM for I(Kur). 293B blocked I(to1) and I(Kur) with the same concentration range, and the significant effect was observed from the concentration of 1 microM. The maximum inhibitive effect was 88% for I(to1) and 96% for I(Kur) at 250 microM. Voltage dependence of activation and inactivation, and time-dependent recovery from inactivation of I(to1) were not altered by 293B; however, time to peak and time-dependent inactivation of I(to1) was significantly accelerated. The results indicate that 293B significantly inhibits the major repolarization K(+) currents I(to1) and I(Kur) in human atrial myocytes.

Chromosomal aberrations of primary lung adenocarcinomas in nonsmokers.

BACKGROUND: Lung carcinoma is a common malignancy, and tobacco carcinogenesis is the major cause. Studies on individual genes or loci have suggested, that in tumors from nonsmokers, different genetic alterations are present compared with tumors from smokers. It is possible that distinct genetic pathways may be involved. However, the targets remain largely unknown; and, to the authors' knowledge, molecular cytogenetics studies on lung carcinomas from nonsmokers have not been reported. METHODS: Comparative genomic hybridization (CGH) analysis was performed on primary lung adenocarcinoma samples from 32 patients who never smoked to identify loci of frequent aberrations. RESULTS: Different extents of aberration were found in 31 of the 32 samples studied. The most frequently altered locus was gain of 16p (59% of samples) followed by gain of 20q (44% of samples), with the minimal overlapping regions at 16p13.1-p13.2 and 20q13.2, respectively. Other over-represented loci with > 30% frequency were observed at 5p (34% of samples), 7p (41% of samples), 8q (31% of samples), 17q (34% of samples), and 19q (34% of samples); and high-level DNA amplifications were detected at 1q, 7p, 12q, 19q, and 20q. DNA under-representation was observed less commonly and included 8p (28% of samples), 9p (22% of samples), 13q (28% of samples), and 18q (38% of samples). CONCLUSIONS: The current study identified targets of frequent genetic aberration in primary adenocarcinomas from nonsmokers. Compared with reported CGH findings in the literature, the current findings suggest that DNA gain at 16p is the distinct aberration involved in these tumors. Other frequently altered loci involve commonly reported oncogenic and tumor suppressor loci, suggesting an overlap with the genetic pathways of tobacco-induced lung carcinogenesis.

Primary adenocarcinomas of the lung in nonsmokers show a distinct pattern of allelic imbalance.

Lung cancer development in nonsmokers, particularly in females, has long been observed,but the genetic pathways of oncogenesis are still unclear. The purpose of this study was to identify important targets of chromosomal alteration involved in non-tobacco-related adenocarcinomas of lung. In this study, loci of recurrent allelic imbalance (AI) were identified by microsatellite analysis, focusing on tumors with low frequencies of AI (FAL) relative to the mean level. We reasoned that studying such tumors would facilitate the identification of essential genetic changes needed for the malignant phenotype, which could be masked by genomic instability and widespread nonspecific alterations, especially in tumors showing high FAL. Forty-two adenocarcinomas from nonsmokers (NT-ADs) were analyzed by a broad spectrum of 84 markers covering all nonacrocentric chromosomal arms. Using the mean AI frequency (40%) as the threshold, loci in 7q31, 8p23.2, 10p14-p15, 13q12.3, 16q24, 17p13.1-p13.3, 17q22, 19q13.3, and Xq11.2-q12 showed recurrent AI in the low-FAL tumors, which suggested that essential targets of carcinogenesis may be present. To analyze whether loci, frequently altered in NT-ADs, were uniquely involved in these tumors, 43 loci were also studied in 29 adenocarcinomas from smokers. 2q, 6p, 10p, 13q, 16q, 17q, 19p, 19q, 20p, and 20q showed frequent aberrations in NT-ADs, whereas 1q, 2p, 3p, 3q, 7q, 8p, 9p, 9q, 10q, 11q, 13q, 14q, TP53, 17p, 18q, and 21q were commonly altered in both of the tumor groups. Further comparison of their low-FAL tumors showed that AI involving 16q24, 17q22, and 19q13.3 were significantly associated with NT-ADs; whereas those involving 7q31, 8p23.2, 10p14-p15, 13q12.3, and 17p13.1-p13.3 were observed in both. The findings suggest that oncogenesis in the lung of smokers and nonsmokers involve overlapping yet distinct genetic pathways, whereas the recurrent loci of alteration in NT-ADs may provide a basis for the further mapping of critical molecular targets in these pathways.