ECG features and proarrhythmic potentials of therapeutic hypothermia.

OBJECTIVE: Hypothermia can induce ECG J waves. Recent studies suggest that J waves may be associated with ventricular fibrillation (VF) in patients with structurally normal hearts. However, little is known about the ECG features, clinical significance or arrhythmogenic potentials of therapeutic hypothermia (TH)-induced J waves. METHODS: We analysed ECGs from 240 patients who underwent TH at six major university hospitals in Korea between August 2010 and December 2013. The prevalence, amplitudes and distributions of the J waves and the development of malignant arrhythmia were analysed. RESULTS: The average patient body temperature was 33.5±1.0°C during TH. J waves were observed in 98 patients (40.8%). They were newly developed in 91 cases, and pre-existing J waves were augmented in seven patients. J waves during TH were primarily observed in leads II, III, aVF and V4-6. The average amplitude of the J waves was 0.239±0.152 mV. There were four VF events during TH. These events occurred in three patients who were finally diagnosed with Brugada syndrome, idiopathic VF or early repolarisation syndrome, respectively, and in one patient with non-cardiac aetiology (asphyxia). CONCLUSIONS: J waves were recorded in about 40% of the patients who received TH. They were most frequently observed in the inferior limb leads or lateral precordial leads. Life-threatening VF occurred only rarely (1.7%) during TH and were mainly observed in patients with primary arrhythmic disorder. Although a causal relationship between TH-induced J waves and VF remains unknown, administering TH to this potentially susceptible, high-risk population may require careful attention.

Achievement of successful pulmonary vein isolation: methods of adenosine testing and incremental benefit of exit block.

PURPOSE: Several approaches were tried to achieve complete pulmonary vein isolation (PVI). The aims of this study were to (1) compare adenosine-induced PV conduction and exit conduction, (2) determine the adequate adenosine dose, and (3) investigate the correlation of dormant conduction and recurrence of atrial fibrillation (AF). METHODS: A total of 378 consecutive patients who underwent PVI from June 2012 to April 2015 were prospectively included (the de novo procedure in 318 (84.1 %) and a redo procedure in 60 (15.9 %)). After the exit block was assessed, 20 mg adenosine was injected into the left atrium. If dormant conduction was observed, 12 and 6 mg of adenosine were injected sequentially. RESULTS: Exit conduction during PV pacing was observed in 34 patients (9 %), and dormant conduction was observed in 92 patients (24.3 %). Among them, 74 (80.4 %, 74/92) demonstrated dormant conduction without exit conduction and 16 (47.1 %, 16/34) showed exit conduction without dormant conduction. The 20-mg dose of adenosine had an additive yield in patients with dormant conduction, compared to that of 12 mg (93 %, 86/92) or 6 mg (80 %, 74/92). There was no significant difference in the recurrence rate regarding dormant conduction. The pattern of prevalence of reconnected origin during the redo procedure was similar to that of dormant conduction during the index procedure. CONCLUSIONS: There was a discrepancy between adenosine-induced PVI and exit block. Therefore, exit block test has additional value to verify latent incomplete PVI in conjunction with adenosine test. Furthermore, high-dose adenosine had an additive yield. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov/ct2/show/NCT01932112.

Second coupling interval of nonsustained ventricular tachycardia to distinguish malignant from benign outflow tract ventricular tachycardias.

BACKGROUND: Idiopathic ventricular tachycardia (VT) originating from the outflow tract (OT) usually is considered a benign condition. In rare cases, patients with OT-VT suffer from syncope or even sudden cardiac death. OT-VT is frequently preceded by nonsustained VT (NSVT). OBJECTIVE: The purpose of this study was to clarify if the ECG parameters of NSVTs could differentiate malignant from benign OT-VT. METHODS: We retrospectively evaluated patients without structural heart disease who had documented OT-NSVT on ECG. ECG parameters were compared between patients with syncope, aborted sudden cardiac death, or ventricular fibrillation (malignant group, n = 36) and patients without syncope (benign group, n = 40). RESULTS: There were no differences with regard to age and gender between the malignant and benign groups. On analysis of NSVT, the first coupling interval (CI) of NSVT was comparable between the 2 groups (458 ± 87 ms vs 485 ± 95 ms, P = .212). However, the second CI of NSVT beats was significantly shorter in the malignant group (313 ± 58 ms vs 385 ± 83 ms, P < .0001). During 48-month follow-up, the benign group had a significantly lower recurrence of clinical VT than the malignant group (P = .046). The malignant group frequently had more than 1 focus of VT, whereas the benign group showed only a single focus (1.82 vs 1.09, P = .023). CONCLUSION: The second CI of NSVT in the malignant group was significantly shorter than that of the benign OT-VT group. Careful measurement of the second CI of NSVT may help identify the malignant form of OT-VT, enabling early treatment to prevent future cardiac events.

Familial hypercholesterolemia and the atherosclerotic disease.

Familial hypercholesterolemia (FH) is associated with premature atherosclerotic cardiovascular diseases, and is inherited as an autosomal dominant trait. The prevalence of heterozygous FH is one in five hundred people. Owing to dysfunctional low density lipoprotein (LDL) receptors due to genetic mutations, serum low density lipoprotein-cholesterol (LDL-C) levels are considerably increased from birth. FH is clinically diagnosed by confirmation of family history and characteristic findings such as tendon xanthoma or xanthelasma. Thus, clinical concern and suspicion are important for early diagnosis of the disease. Current guidelines recommend lowering LDL-C concentration to at least 50% from baseline. Statins are shown to lower LDL-C levels with high safety, and thus, have been the drug of choice. However, it is difficult to achieve an ideal level of LDL-C with a single statin therapy in the majority of FH patients. Alternatively, lipid lowering combination therapy with the recently-introduced ezetimibe has shown more encouraging results.

Influence of diabetes mellitus on long-term (five-year) outcomes of drug-eluting stents and coronary artery bypass grafting for multivessel coronary revascularization.

Diabetes mellitus is a major risk factor for coronary artery disease (CAD) and for diffuse and progressive atherosclerosis. We evaluated the outcomes of drug-eluting stent (DES) placement and coronary artery bypass grafting (CABG) in 891 diabetic patients (489 for DES implantation and 402 for CABG) and 2,151 nondiabetic patients (1,058 for DES implantation and 1,093 for CABG) with multivessel CAD treated from January 2003 through December 2005 and followed up for a median 5.6 years. Outcomes of interest included death; the composite outcome of death, myocardial infarction (MI), or stroke; and repeat revascularization. In diabetic patients, after adjusting for baseline covariates, 5-year risk of death (hazard ratio 1.01, 95% confidence interval 0.77 to 1.33, p = 0.96) and the composite of death, MI, or stroke (hazard ratio 1.03, 95% confidence interval 0.80 to 1.31, p = 0.91) were similar in patients undergoing DES or CABG. However, rate of repeat revascularization was significantly higher in the DES group (hazard ratio 3.69, 95% confidence interval 2.64 to 5.17, p <0.001). These trends were consistent in nondiabetic patients (hazard ratio 0.80, 95% confidence interval 0.55 to 1.16, p = 0.23 for death; hazard ratio 0.77, 95% confidence interval 0.56 to 1.05, p = 0.10 for composite of death, MI, or stroke; hazard ratio 2.77, 95% CI 1.95 to 3.91, p <0.001 for repeat revascularization). There was no significant interaction between diabetic status and treatment strategy on clinical outcomes (p for interaction = 0.36 for death; 0.20 for the composite of death, MI, or stroke; and 0.40 for repeat revascularization). In conclusion, there was no significant prognostic influence of diabetes on long-term treatment with DES or CABG in patients with multivessel CAD.

Somatic mutations of the KEAP1 gene in common solid cancers.

AIMS: KEAP1 inhibits nuclear factor erythroid 2-related factor 2 (NRF2)-induced cytoprotection, and is considered to be a candidate tumour suppressor. Somatic mutation of NRF2 has been analysed in a wide variety of human cancers, whereas somatic mutation of KEAP1 has been reported only in lung and gall bladder cancers. The aim of our study was to investigate whether KEAP1 mutations are widespread in human cancers. METHODS AND RESULTS: We analysed 499 cancer tissues from lung, breast, colon, stomach, liver, larynx and prostate, and leukaemias, by single-strand conformation polymorphism analysis. We detected somatic mutations of KEAP1 in gastric (11.1%), hepatocellular (8.9%), colorectal (7.8%), lung (4.6%), breast (2.0%) and prostate (1.3%) carcinomas. Allelic losses of the KEAP1 locus were identified in 42.9% of cancers with KEAP1 mutations, but no NRF2 mutations were detected in these cancers. The NRF2-activated cytoprotective proteins (NAD(P)H dehydrogenase quinone 1 and glutamine-cysteine ligase catalytic subunit) were expressed in all of the cancers with KEAP1 mutations. CONCLUSIONS: Our data show that KEAP1 mutations occur widely in solid cancers, irrespective of histological type. Biallelic inactivation of KEAP1 and increased levels of cytoprotective proteins in the cancers suggest that KEAP1 mutations might protect cancer cells from oxidative insults and play a role in the development of solid cancers.

Somatic mutation of PHF6 gene in T-cell acute lymphoblatic leukemia, acute myelogenous leukemia and hepatocellular carcinoma.

INTRODUCTION: Somatic mutations in plant homeodomain finger protein 6 (PHF6) gene have recently been reported in T-cell acute lymphoblastic leukemia (T-ALL), strongly suggesting its role in the pathogenesis of human cancers. MATERIALS AND METHODS: To see whether the PHF6 mutation occurs in other malignancies, we analyzed entire coding sequences of PHF6 in 231 hematologic malignancies [105 acute myelogenous leukemias (AML), 66 pre-B-ALL, 23 T-ALL, one undifferentiated acute leukemia and 36 multiple myelomas] by single-strand conformation polymorphism assay. Also, we analyzed the mutation in 236 solid cancers, including 41 lung, 39 hepatocellular (HCC), 36 breast, 40 colorectal, 40 gastric and 40 prostate carcinomas. RESULTS: In the hematologic malignancies, there were 11 PHF6 mutations that were detected not only in T-ALL (34.7%) (five adult and three childhood T-ALL), but also in two AML (1.9%) (one acute monocytic leukemia and one AML minimally differentiated). In addition, there was a PHF6 mutation in the HCC (2.6%). The PHF6 mutations were detected in both male and female patients, and consisted of six frameshift, three nonsense and two intron mutations. CONCLUSION: Our data suggest that PHF6 mutation might play a role in tumorigenesis not only of T-ALL, but also of AML and HCC.

Frameshift mutations of vacuolar protein sorting genes in gastric and colorectal cancers with microsatellite instability.

Vacuolar protein sorting plays crucial roles in the traffic of molecules between cellular organelles. Although involvement of vacuolar protein sorting proteins in cancer is known, genetic alterations of VPS genes have not been reported in cancers. We found that VPS4B, VPS13A, VPS13B, VPS13C, VPS33A, VPS35, VPS37B, VPS37D, VPS41, and VPS54 have mononucleotide repeats in their coding sequences. To see whether these genes are mutated in cancers with microsatellite instability, we analyzed the mononucleotide repeats in 30 gastric cancers with high microsatellite instability, 13 gastric cancers with low microsatellite instability, and 45 gastric cancers with stable microsatellites and 40 colorectal cancers with high microsatellite instability, 14 colorectal cancers with low microsatellite instability, and 45 colorectal cancers with stable microsatellites by single-strand conformation polymorphism. We found mutations of VPS13A, VPS13B, VPS13C, VPS33A, VPS35, VPS37B, VPS41, and VPS54 in 9, 3, 12, 3, 5, 9, 2, and 2 cancers, respectively, all in cancers with high microsatellite instability. The gastric cancers and colorectal cancers with high microsatellite instability harbored one or more mutations of the VPS genes in 53.3% and 50.0%, respectively. Loss of Vps13A expression was observed in 30% of the gastric cancers and 35% of the colorectal cancers, whereas loss of Vps35 was observed in 55% of the gastric cancers and 55% of the colorectal cancers. Our data indicate that frameshift mutations of VPS genes and losses of expression of Vps13A and Vps35 proteins are common in gastric cancers and colorectal cancers with high microsatellite instability and suggest that these alterations might contribute to development of cancers with high microsatellite instability by deregulating vacuolar protein sorting proteins.

Expression of AIMP1, 2 and 3, the scaffolds for the multi-tRNA synthetase complex, is downregulated in gastric and colorectal cancer.

Aminoacyl-tRNA synthetase-interacting multifunctional proteins (AIMPs) form a protein complex with aminoacyl-tRNA synthetases. In addition to protein translation, AIMPs play a role in diverse biological processes. Earlier studies suggested that AIMPs may act as tumor suppressors. However, the expression status of the AIMP proteins in human cancer tissues is largely unknown. In this study, we analyzed the expression of AIMP members (AIMP1, AIMP2 and AIMP3) in gastric cancer (GC) and colorectal cancer (CRC) tissues. We analyzed the expression of these proteins in 100 GC and 103 CRC tissues by immunohistochemistry using a tissue microarray method. Normal gastric and colon mucosa expressed AIMP1, AIMP2 and AIMP3 in nearly all of the cases (95-100%). However, the expression of AIMP1, AIMP2 and AIMP3 was significantly decreased in the GC samples (60%, 52% and 70% of the cases, respectively) and in the CRC samples (66%, 53% and 81% of the cases, respectively) ( P <0.01). Expression of AIMP1, AIMP2 or AIMP3 was not associated with clinicopathological parameters including differentiation, depth of invasion and TNM stage. The decreased expression of AIMP1, AIMP2 and AIMP3 in the GC and CRC tissues compared to the corresponding normal tissues suggested that downregulation of these proteins may be related to inactivation of the tumor suppressor functions of AIMP proteins and might play a role in the development of GC and CRC.

Penetration of the digital nerves by the common palmar digital arteries in human cadavers.

PURPOSE: To investigate the incidence of digital nerve loop penetration by digital arteries (neural loops) in cadaver palms and to classify these neural loops according to their topography and morphology. METHODS: In total, 121 palms (from 57 right and 64 left hands) were dissected from 70 preserved cadavers (50 male and 20 female; mean age 66.1 y). RESULTS: Of the 121 palms, 98 had neural loops; 184 cases of neural loop were observed in total. The neural loops could be classified into 4 topographical types, according to their position relative to the digital arteries: ulnar (in which the ulnar proper palmar digital nerve of the finger is penetrated), radial (in which the radial proper palmar digital nerve of the finger is penetrated), common (in which the common palmar digital nerve of the finger is penetrated), and bridge (in which the neural loop is formed by connecting the ulnar and radial proper palmar digital nerves). The neural loops were also classified morphologically according to their size: form A (≥10 mm), form B (4.0-9.9 mm), and form C (≤3.9 mm). The mean lengths in these groups were 16.1, 7.2, and 3.0 mm, respectively, and the overall mean length of all neural loops was 10.8 mm. CONCLUSIONS: It was confirmed that neural loops are a common occurrence in humans; hence, it is surprising that it is a little-known variation in the palm.