Syphilis and cardiovascular risk: a Taiwanese registry.

BACKGROUND AND AIMS: Studies on the impact of syphilis on the cardiovascular system in large populations are limited. This study investigated the effects of syphilis on cardiovascular outcomes. METHODS: Medical records from 2010 to 2015 were retrieved from the Taiwan National Health Insurance Research Database, linked to the Notifiable Infectious Diseases database from the Taiwan Centers for Disease Control. Patients with syphilis were identified, excluding those with missing information, under 20 years of age, or with a history of human immunodeficiency virus infection, acute myocardial infarction, heart failure, aortic regurgitation, replacement of the aortic valve, aneurysm and/or dissection of the aorta, atrial fibrillation, ischaemic stroke, haemorrhagic stroke, and venous thromboembolism. Primary outcomes included new-onset acute myocardial infarction, heart failure, aortic regurgitation, aneurysm and dissection of the aorta, atrial fibrillation, ischaemic stroke, haemorrhagic stroke, venous thromboembolism, cardiovascular death, and all-cause mortality. RESULTS: A total of 28 796 patients with syphilis were identified from 2010 to 2015. After exclusions and frequency matching, 20 601 syphilis patients and 20 601 non-syphilis patients were analysed. The relative rate (RR) was utilized in the analysis, as the competing risk of death was not considered. Compared with patients without syphilis, patients with syphilis had increased risks of acute myocardial infarction (RR 38%, 95% confidence interval [CI] 1.19-1.60, P < .001), heart failure (RR 88%, 95% CI 1.64-2.14, P < .001), aortic regurgitation (RR 81%, 95% CI 1.18-2.75, P = .006), atrial fibrillation (RR 45%, 95% CI 1.20-1.76, P < .001), ischaemic stroke (RR 68%, 95% CI 1.52-1.87, P < .001), haemorrhagic stroke (RR 114%, 95% CI 1.74-2.64, P < .001), venous thromboembolism (RR 67%, 95% CI 1.23-2.26, P = .001), cardiovascular death (RR 155%, 95% CI 2.11-3.08, P < .001), and all-cause death (RR 196%, 95% CI 2.74-3.19, P < .001) but not for aneurysm and dissection of the aorta. CONCLUSIONS: This study demonstrates that patients with syphilis have a higher risk of cardiovascular events and all-cause mortality compared with those without syphilis.

Association of Valve Size and Hemodynamic Performance With Clinical Outcomes in Aortic Valve Replacement　- A Long-Term Follow-up in an Asian Population.

BACKGROUND: Studies of the influence of smaller body type on the severity of prosthesis-patient mismatch (PPM) after small-sized surgical aortic valve replacement (SAVR) are few, but the issue is particularly relevant for Asian patients.Methods and Results: 695 patients who underwent SAVR with bioprosthetic valves had their hemodynamic valve performance analyzed at 3 months, 1 year, 3 years, and 5 years after operation, and clinical outcomes were assessed. The patients were stratified into 3 valve size groups: 19/21, 23, and 25/27 mm. A smaller valve was associated with higher mean pressure gradients at the 4 time points after operation (P trend <0.05). However, the 3 valve size groups demonstrated no significant differences in the risk of clinical events. At none of the time points did patients with projected PPM show increased mean pressure gradients (P>0.05), whereas patients with measured PPM did (P<0.05). Compared with patients with projected PPM, those with measured PPM demonstrated higher rates of infective endocarditis readmission (adjusted hazard ratio [aHR] 3.31, 95% confidence interval [CI] 1.06-10.39) and a higher risk of composite outcomes (aHR 1.45, 95% CI 0.95-2.22, P=0.087). CONCLUSIONS: Relative to those receiving larger valves, patients receiving small bioprosthetic valves had poorer hemodynamic performance but did not demonstrate differences in clinical events in long-term follow-up.

Mitral Valve Repair vs. Replacement by Different Etiologies　- A Nationwide Population-Based Cohort Study.

BACKGROUND: When mitral valve (MV) surgery is indicated, repair is preferred over replacement; however, this preference is not supported by evidence from clinical trials. Furthermore, the benefits of MV repair may not be universal for all etiologies of MV disease. METHODS AND RESULTS: This study identified a total of 18,428 patients who underwent MV repair (n=4,817) or MV replacement (n=13,611) during 2001-2018 from Taiwan's National Health Insurance Research Database. These patients were classified into 4 etiologies: infective endocarditis (IE, n=2,678), rheumatic heart disease (RHD, n=4,524), ischemic mitral regurgitation (IMR, n=3,893), and degenerative mitral regurgitation (DMR, n=7,333). After propensity matching, all-cause mortality during follow-up was lower among patients receiving MV repair than among patients receiving MV replacement in the IE, IMR, and DMR groups (hazard ratio [HR]=0.72, 95% confidence interval [CI]: 0.55-0.93; HR=0.82, 95% CI: 0.73-0.92; and HR 0.73, 95% CI: 0.64-0.84, respectively). However, in the RHD group, the MV reoperation rate was higher after MV repair than after MV replacement (subdistribution HR=1.91, 95% CI: 1.02-3.55). CONCLUSIONS: In comparison with MV replacement, MV repair was associated with a lower late mortality in patients with IE, IMR, and DMR, and a higher risk of reoperation in patients with RHD.

Outcomes of Endovascular Treatment for Infective Aortic Aneurysms　- A Multicenter Retrospective Study.

BACKGROUND: In Taiwan, infective native aortic aneurysms (INAAs) are relatively common, so the aim of present study was to demonstrate the comparative outcomes of endovascular repair for thoracic and abdominal INAAs.Methods and Results: Patients with naïve thoracic or abdominal INAAs managed with endovascular repair between 2001 and 2018 were included in this multicenter retrospective cohort. The confounding factors were adjusted with propensity score (PS). Of the 39 thoracic and 43 abdominal INAA cases, 41 (50%) presented with aneurysmal rupture, most of which were at the infrarenal abdominal (n=35, 42.7%) or descending thoracic aorta (n=25, 30.5%). Salmonella spp. was the most frequently isolated pathogen. The overall in-hospital mortality rate was 18.3%. The risks of in-hospital death and death due to rupture were significantly lower with thoracic INAAs (12.8% vs. 23.3%; PS-adjusted odds ratio (OR) 0.24, 95% confidence interval (CI) 0.06-0.96; 0.1% vs. 9.3%; PS-adjusted OR 0.11, 95% CI 0.01-0.90). During a mean follow-up of 2.5 years, the risk of all-cause death was significantly higher with thoracic INAAs (35.3% vs. 15.2%; PS-adjusted HR 6.90, 95% CI 1.69-28.19). Chronic kidney disease (CKD) was associated with death. CONCLUSIONS: Compared with thoracic INAAs, endovascular repair of abdominal INAAs was associated with a significantly higher in-hospital mortality rate. However, long-term outcomes were worse for thoracic INAAs, with CKD and infections being the most important predictor and cause of death, respectively.

Surgical volume and outcomes of surgical ablation for atrial fibrillation: a nationwide population-based cohort study.

BACKGROUND: Atrial fibrillation is the most common cardiac arrythmia and causes many complications. Sinus rhythm restoration could reduce late mortality of atrial fibrillation patients. The Maze procedure is the gold standard for surgical ablation of atrial fibrillation. Higher surgical volume has been documented with favorable outcomes of various cardiac procedures such as mitral valve surgery and aortic valve replacement. We aimed to determine the volume-outcome relationship (i.e., association between surgical volume and outcomes) for the concomitant Maze procedure during major cardiac surgeries. METHODS: This nationwide population-based cohort study retrieved data from the Taiwan National Health Insurance Research Database. Adult patients undergoing concomitant Maze procedures during 2010-2017 were identified; consequently, 2666 patients were classified into four subgroups based on hospital cumulative surgery volumes. In-hospital outcomes and late outcomes during follow-up were analyzed. Logistic regression and Cox proportional hazards model were used to analyze the volume-outcome relationship. RESULTS: Patients undergoing Maze procedures at lower-volume hospitals tended to be frailer and had higher comorbidity scores. Patients in the highest-volume hospitals had a lower risk of in-hospital mortality than those in the lowest-volume hospitals [adjusted odds ratio, 0.30; 95% confidence interval (CI), 0.15-0.61; P < 0.001]. Patients in the highest-volume hospitals had lower rates of late mortality than those in the lowest-volume hospitals, including all-cause mortality [adjusted hazard ratio (aHR) 0.53; 95% CI 0.40-0.68; P < 0.001] and all-cause mortality after discharge (aHR 0.60; 95% CI 0.44-0.80; P < 0.001). CONCLUSIONS: A positive hospital volume-outcome relationship for concomitant Maze procedures was demonstrated for in-hospital and late follow-up mortality. The consequence may be attributed to physician skill/experience, experienced multidisciplinary teams, and comprehensive care processes. We suggest referring patients with frailty or those requiring complicated cardiac surgeries to high-volume hospitals to improve clinical outcomes. TRIAL REGISTRATION: the institutional review board of Chang Gung Memorial Hospital approved all data usage and the study protocol (registration number: 202100151B0C502).

Influence of chronic obstructive pulmonary disease on long-term hospitalization and mortality in patients with heart failure with reduced ejection fraction.

BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) can coexist with chronic obstructive pulmonary disease (COPD), which complicates the clinical situation and worsens quality of life. The study used standard diagnostic criteria for detecting COPD in hospitalized HFrEF patients and to survey the influence of other comorbidities and medications on the long-term outcomes of HFrEF + COPD patients. METHODS: We retrospectively recruited patients hospitalized due to HFrEF in a tertiary medical center and examined and followed up clinical outcomes, including length of hospital stay, mortality, and readmission episodes, for a 5-year period. Risk factors for mortality were analyzed using multivariate analysis. RESULTS: Of the 118 hospitalized HFrEF study participants, 68 had concurrent COPD whereas 50 did not. There was a significant increase in the male predominance, smoking history, higher hemoglobin level and increased length of hospital stay in the HF + COPD group than in the HF-only group. Lower left ventricular ejection fraction was found in the HF and COPD comorbidity group. In multivariate analysis, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) use independently associated with a beneficial effect on survival in HF patients with COPD. Oral corticosteroid uses and stroke as a comorbidity were independently associated with a shorter time to the first readmission episode. CONCLUSION: In HFrEF patients, COPD was associated with a prolonged length of hospital stay. ACEI/ARB use might relate to a beneficial effect on survival in HF patients with COPD. The use of maintenance oral corticosteroid in patients with both HF and COPD should be crucially evaluated to determine the clinical benefit and disadvantages.

Regulation of autophagy in leukocytes through RNA N6-adenosine methylation in chronic kidney disease patients.

Patients with chronic kidney diseases have multiple cellular dysfunctions leading to increased atherosclerosis, impaired immunity, and disturbed metabolism. However, it is unclear what is the fundamental signaling served as a marker or as a mediator for the dysregulated function in their leukocytes or tissues. Here we hypothesized that the N6-Methyladenosine (m6A) modification of the RNA in the leukocytes is responsible for the cellular dysfunction in chronic kidney diseases. Patients with chronic kidney diseases had significantly less m6A abundances in leukocytes and elevated RNA demethylase FTO proteins. The uremic toxin, indoxyl sulfate, activated the autophagy flux through modulation of FTO and m6A modifications in RNA. Notably, knockdown of FTO or inhibit the m6A by 3-deazaadenosine blocks the effects of indoxyl sulfate on autophagy activation in cells. These findings provide new insights into the mechanisms underlying chronic kidney disease-associated cellular dysfunction. Targeting RNA m6A modification may be a novel strategy for the treatment of chronic kidney diseases and autophagy.

Angiographic Complete versus Clinical Selective Incomplete Percutaneous Revascularization in Heart Failure Patients with Multivessel Coronary Disease.

BACKGROUND: Patients with multivessel disease (MVD) often pursue complete revascularization (CR) during percutaneous coronary intervention (PCI) to improve prognosis. However, angiographic CR is not always feasible and is associated with some procedure-related complications in heart failure (HF) patients with MVD. Clinical selective incomplete revascularization (IR) may be reasonable for these high-risk patients, but its role in long-term outcomes remains uncertain. METHODS: Six hundred patients with HF and MVD submitted to PCI were enrolled. Major adverse cardiac events (MACEs) were defined as a composite of recurrent myocardial infarction, any revascularization, and all-cause mortality at 5 years. RESULTS: During a mean follow-up period of 3.7 ± 1.9 years, there was no significant difference in 5-year MACEs between selective IR and successful angiographic CR in HF patients with MVD. However, patients who failed CR had a significantly greater incidence of 5-year MACEs than those in the other two groups (failed CR: 46.4% vs. selective IR: 27.7% vs. successful CR: 27.8%, p < 0.001). CONCLUSIONS: Long-term outcomes of selective IR were comparable with those of successful angiographic CR in HF patients with MVD. However, patients that failed CR showed 2.53-fold increased risk of MACEs compared to patients undergoing either selective IR or successful angiographic CR. A more comprehensive planning strategy should be devised before PCI in HF patients with MVD.

The role of Asprosin in patients with dilated cardiomyopathy.

BACKGROUND: Asprosin is a novel fasting glucogenic adipokine discovered in 2016. Asprosin induces rapid glucose releases from the liver. However, its molecular mechanisms and function are still unclear. Adaptation of energy substrates from fatty acid to glucose is recently considered a novel therapeutic target in heart failure treatment. We hypothesized that the asprosin is able to modulate cardiac mitochondrial functions and has important prognostic implications in dilated cardiomyopathy (DCM) patients. METHODS: We prospectively enrolled 50 patients (86% male, mean age 55 ± 13 years) with DCM and followed their 5-year major adverse cardiovascular events from 2012 to 2017. Comparing with healthy individuals, DCM patients had higher asprosin levels (191.2 versus 79.7 ng/mL, P < 0.01). RESULTS: During the 5-year follow-up in the study cohort, 16 (32.0%) patients experienced adverse cardiovascular events. Patients with lower asprosin levels (< 210 ng/mL) were associated with increased risks of adverse clinical outcomes with a hazard ratio of 7.94 (95% CI 1.88-33.50, P = 0.005) when compared patients with higher asprosin levels (≥ 210 ng/mL). Using cardiomyoblasts as a cellular model, we showed that asprosin prevented hypoxia-induced cell death and enhanced mitochondrial respiration and proton leak under hypoxia. CONCLUSIONS: In patients with DCM, elevated plasma asprosin levels are associated with less adverse cardiovascular events in five years. The underlying protective mechanisms of asprosin may be linked to its functions relating to enhanced mitochondrial respiration under hypoxia.

Comparison of 9-Month Angiographic Follow-Up and Long-Term Clinical Outcomes of Biodegradable Polymer Drug-Eluting Stents and Second-Generation Durable Polymer Drug-Eluting Stents in Patients Undergoing Single Coronary Artery Stenting.

BACKGROUND: The durable polymers (DP) used in first-generation drug-eluting stents (DESs) were associated with long-term cardiovascular events, and thus biodegradable polymer DESs (BP-DESs) and second-generation DP-DESs were designed to overcome this problem. In this study, we compared angiographic follow-up and long-term clinical outcomes between patients who received BP-DESs or second-generation DP-DESs. METHODS: We enrolled 436 patients with single coronary lesions who received a second-generation DP-DES or BP-DES between June 2009 and October 2012. All patients received follow-up angiography when new clinical events developed or at 9 months after index stenting. All participants received follow-up for 5 years. RESULTS: There were no significant differences in patient and lesion characteristics between the two groups. The 9-month angiographic follow-up showed a lower net gain in the second-generation DP-DES group (2.19 mm vs. 2.41 mm, p = 0.040), but a similar binary restenosis rate between the two groups (5.4% vs. 8.7%, p = 0.276). During the 5-year follow-up period, no significant differences were observed between the two groups in major adverse cardiac events (MACEs), cardiovascular death, nonfatal myocardial infarction (MI), target vessel revascularization (TVR), all revascularization, stent thrombosis (ST), or MACE-free survival. CONCLUSIONS: No significant differences were observed in cardiovascular death, nonfatal MI, TVR, all revascularization, ST, or MACE-free survival between the patients undergoing single coronary artery stenting with BP-DESs and second-generation DP-DESs.

Complete and incomplete revascularization in non-ST segment myocardial infarction with multivessel disease: long-term outcomes of first- and second-generation drug-eluting stents.

The therapeutic effects of reperfusion strategies with complete revascularization (CR) or incomplete revascularization (IR) in non-ST segment myocardial infarction (NSTEMI) patients with multivessel disease (MVD) are controversial. In such patients, whether utilization of different generations of drug-eluting stents (DES) for IR or CR affect long-term major adverse cardiovascular events (MACE) is unknown. This study included 702 NSTEMI patients with MVD who received first-generation (1G) or second-generation (2G) DES. In multivariable analysis, chronic kidney disease, chronic total, 1G DES and IR were independent predictors of long-term MACE. In patients receiving 1G DES, no significant differences of MACE were observed between the IR and CR groups (39.1% vs. 36.2%, p = 0.854). However, in patients receiving 2G DES, significantly fewer MACE were observed in the CR group than in the IR group (3.7% vs. 10.2%, p = 0.002). Compared with patients receiving 1G DES for IR, those receiving 2G DES for IR and CR exhibited significantly lower risk of MACE (59% and 83% lower, respectively). CR could not provide clinical benefits over IR in NSTEMI patients with MVD receiving 1G DES. However, in patients receiving 2G DES, compared with IR, CR was associated with a lower risk of long-term MACE, which was mainly caused by low rates of non-TLR and any revascularization.

Targeted Next Generation Sequencing for Genetic Mutations of Dilated Cardiomyopathy.

BACKGROUND: Approximately one-third of cases of dilated cardiomyopathy (DCM) are caused by genetic mutations. With new sequencing technologies, numerous variants have been associated with this inherited cardiomyopathy, however the prevalence and genotype-phenotype correlations in different ethnic cohorts remain unclear. This study aimed to investigate the variants in Chinese DCM patients and correlate them with clinical presentations and prognosis. METHODS AND RESULTS: From September 2013 to December 2016, 70 index patients underwent DNA sequencing for 12 common disease-causing genes with next generation sequencing. Using a bioinformatics filtering process, 12 rare truncating variants (7 nonsense variants, 4 frameshift variants, and 1 splice site variant) and 29 rare missense variants were identified. Of these, 3 patients were double heterozygotes and 10 patients were compound heterozygotes. Overall, 47.1% (33/70) of the index patients had the seputatively pathogenic variants. The majority (33/41, 80.4%) of these variants were located in titin (TTN). More than 80% of the TTN variants (27/33, 81.8%) were distributed in the A band region of the sarcomere. Patients carrying these variants did not have a different phenotype in disease severity, clinical outcome and reversibility of ventricular function compared with non-carriers. CONCLUSIONS: Several new rare variants were identified in a Chinese population in this study, indicating that there are ethnic differences in genetic mutations in DCM patients. TTN remains the major disease-causing gene. Our results could be a reference for future genetic tests in Chinese populations. No specific genotype-phenotype correlations were found, however a prospective large cohort study may be needed to confirm our findings.

Excessive irisin increases oxidative stress and apoptosis in murine heart.

Irisin is an exercise-related myokine. The abundance of irisin is associated with many diseases, such as myocardial infarction, chronic kidney disease, metabolic syndrome, obesity, and diabetes mellitus. In cardiomyocytes, irisin modulates the mitochondrial thermogenesis, regulates ischemic responses, and affects calcium signaling. Previous studies suggested that irisin increases cardiomyoblast mitochondrial functions and protects ischemic and reperfusion injury in ex vivo murine heart. In human, clinical studies have shown that acute myocardial infarction patients with more elevated serum irisin abundances are associated with increased major adverse cardiovascular events. However, the mechanisms responsible for this discrepancy between in myocardial infarction patients and ex vivo murine heart is unclear. Based on the clinical observations, we hypothesized that excessive irisin might lead to mitochondrial dysfunctions and cardiomyocyte damages. Our data showed that overexpression of irisin in mice with the adenovirus resulted in enhanced mitochondrial respiration with a higher oxygen consumption rate. Enhanced irisin expression in heart and irisin treatment in cardiomyocytes increased reactive oxygen species production. Furthermore, irisin treatment in cardiomyocytes enhanced the apoptosis and the cleaved caspase 9 levels in hypoxic condition. Pathway analysis in the murine heart with the overexpression of irisin showed that angiopoietin-Tie2, IL-8, IL-13, TGF-ß, and thrombopoietin signaling were affected by irisin. Collectively, these results supported that excessive irisin causes mitochondrial overdrive with a higher reactive oxygen species production, which results in increased apoptosis of cardiomyocytes in a hypoxic environment.

Predictors of Long-Term Outcomes After Drug-Eluting Balloon Angioplasty for Bare-Metal Stent Restenosis.

BACKGROUND: Clinical trials have investigated efficacy of drug-eluting balloon (DEB) angioplasty for bare-metal stent (BMS) in-stent restenosis (ISR). Few studies have investigated predictors of long-term outcomes following BMS-ISR treatment with DEB. METHODS: From June 2011 to April 2015, 105 patients with 125 BMS-ISR lesions were enrolled from the Cardiovascular Atherosclerosis and Percutaneous TrAnsluminal INterventions (CAPTAIN) registry. All these lesions were treated with DEB angioplasty as final therapy. The major adverse cardiac events (MACEs) were recurrent clinically driven target lesion revascularisation (TLR), myocardial infarction, and cardiac death after DEB angioplasty. RESULTS: After DEB angioplasty, the angiographic stenosis decreased from 84.8%±12.4% to 22.6%±10.4%. Over a mean follow-up duration of 21.7±13.4months, the rates of TLR at 1-12 months and 12-48 months were 4.8% and 4.2%, respectively. The rates of MACEs at 1-12 months and 12-48 months were 6.7% and 6.1%, respectively. Chronic haemodialysis, calcified lesion, chronic total occlusion lesion before stenting, stent with metal-to-artery ratio >16.5%, and residual stenosis >25% after DEB angioplasty were potential risk factors for MACEs in univariate analysis. After adjustment in multivariate analysis, independent predictors of long-term MACEs were identified as chronic haemodialysis, chronic total occlusion lesion before stenting, and residual stenosis >25% after DEB angioplasty. CONCLUSIONS: The long-term results of DEB angioplasty for BMS-ISR are acceptable in this real-world registry. Patient (chronic haemodialysis), lesion (chronic total occlusion) and angioplasty (residual stenosis percentage) related factors predicted long-term outcomes following BMS-ISR treatment with DEB angioplasty.

CLOCK modulates survival and acute lung injury in mice with polymicrobial sepsis.

Polymicrobial sepsis is a potentially fatal condition and a significant burden on health care systems. Acute lung injury is the most common complication of sepsis and results in high mortality. However, there has been no recent significant progress in the treatment of sepsis or acute lung injury induced by sepsis. Here we show that mice deficient in the circadian protein CLOCK had better survival than wild-type mice after induction of polymicrobial sepsis by cecal ligation and puncture. Inflammatory cytokine production was attenuated and bacterial clearance was improved in CLOCK-deficient mice. Moreover, acute lung injury after induction of sepsis was significantly decreased in CLOCK-deficient mice. Genome-wide profiling analysis showed that inhibin signaling was reduced in CLOCK-deficient mice. These data establish the importance of circadian CLOCK-inhibin signaling in sepsis, which may have potential therapeutic implications.

Circadian CLOCK Mediates Activation of Transforming Growth Factor-ß Signaling and Renal Fibrosis through Cyclooxygenase 2.

The circadian rhythm regulates blood pressure and maintains fluid and electrolyte homeostasis with central and peripheral clock. However, the role of circadian rhythm in the pathogenesis of tubulointerstitial fibrosis remains unclear. Here, we found that the amplitudes of circadian rhythm oscillation in kidneys significantly increased after unilateral ureteral obstruction. In mice that are deficient in the circadian gene Clock, renal fibrosis and renal parenchymal damage were significantly worse after ureteral obstruction. CLOCK-deficient mice showed increased synthesis of collagen, increased oxidative stress, and greater transforming growth factor-ß (TGF-ß) expression. TGF-ß mRNA expression oscillated with the circadian rhythms under the control of CLOCK-BMAL1 heterodimers. The expression of cyclooxygenase 2 was significantly higher in kidneys from CLOCK-deficient mice with ureteral obstruction. Treatment with a cyclooxygenase 2 inhibitor celecoxib significantly improved renal fibrosis in CLOCK-deficient mice. Taken together, these data establish the importance of the circadian rhythm in tubulointerstitial fibrosis and suggest CLOCK/TGF-ß signaling as a novel therapeutic target of cyclooxygenase inhibition.

Conjunction of Endocardial and Coronary Venous System Mapping to Ablate Ventricular Arrhythmias.

BACKGROUND: Ablation of idiopathic ventricular arrhythmias (VAs) with epicardial or intramural origins is technically challenging. Herein, we have described the successful ablation of left VAs via the coronary venous system (CVS) in conjunction with endocardial map guided by three-dimensional electroanatomical map in six patients. METHODS: Out of a total consecutive 84 patients with symptomatic idiopathic VAs, radiofrequency ablation via the CVS was performed on six patients (7%). Furthermore, we reviewed patient records and electrophysiologic studies with respect to clinical characteristics. RESULTS: Activation map was conducted in 5 patients, and the earliest activation sites were identified within the CVS. The preceding times to the onset of QRS complex were longer than those at the earliest endocardial sites (36.2 ± 5.6 ms vs. 14.2 ± 6.4 ms, p = 0.02, n = 5). Spiky fractionated long-duration potentials were recorded at the successful ablation sites in all 5 patients. The other patient received pacemapping only because of few spontaneous VAs during the procedure, and the best pacemap spot was found within the CVS. Irrigated catheters were required in 4 out of 6 patients because VAs were temporarily suppressed with regular ones. CONCLUSIONS: Idiopathic VAs can be ablated via the CVS in conjunction with endocardial mapping. Additionally, spiky fractionated long-duration potential can function as a clue to identify the good ablation site.

Circadian rhythm of RNA N6-methyladenosine and the role of cryptochrome.

Methylation of RNA N(6)-methyladenosine has fundamental cellular functions, including translation regulation, RNA export, and stem cells renewal. However, the regulation of RNA N(6)-methyladenosine methylation is poorly understood. Here, we observed a robust circadian rhythm in N(6)-methyladenosine modifications of RNA. Deficiency of core mammalian clock genes, cryptochromes, decreased the levels of N(6)-methyladenosine in RNA. Cryptochrome1/2 knockout mice had significantly lower N(6)-methyladenosine methylation of RNA and lost the circadian rhythm of N(6)-methyladenosine levels in RNA. Global analysis of the circadian methylomes of N(6)-methyladenosine in RNA revealed that gene transcription, translation regulation, and RNA metabolism were highly correlated with N(6)-methyladenosine oscillation. Our findings extended a fundamental link between the circadian rhythm and N(6)-methyladenosine modification of RNA and suggested that this link is critical in controlling post-transcriptional gene expression and RNA metabolism.

Prognostic Significance of Phenylalanine in Heart Failure: Clinical Insights and Inter-Organ Crosstalk Snapshot.

Background: Heart failure (HF) remains a leading cause of morbidity and mortality globally, necessitating the identification of reliable prognostic biomarkers to guide therapeutic interventions. Recent clinical observations have underscored phenylalanine (PHE) as a prognostic marker in HF, although the mechanisms involving inter-organ crosstalk remain understood. Methods: This study adopted a dull approach, with a retrospective analysis of 550 HF patients to establish the prognostic value of pre-discharge PHE levels and a study on the inter-organ crosstalk of PHE among 24 patients. We analyzed the correlations between PHE concentrations and clinical outcomes, alongside a comprehensive examination of PHE metabolism across the skeletal muscle, liver, heart, kidney, and lung. Results: In the clinical prognostic analysis of 550 patients hospitalized for acute decompensated HF, elevated PHE levels (≥65.6 µM) were significantly and independently associated with increased all-cause mortality during a median follow-up of 4.5 years (log rank = 36.7, p < 0.001), underscoring its value as a prognostic marker in HF. The inter-organic crosstalk study elucidated the mechanism associated with PHE elevation in patients with HF, characterized by an increase in PHE output in skeletal muscle and a decrease in hepatic and cardiac PHE uptakes. Notably, PHE concentration gradients across these organs were correlated with HF severity, such as the NYHA functional class, B-type natriuretic peptide levels, and the presence of acute HF. Conclusions: Our findings confirm the prognostic significance of PHE in patients with HF and unveil the complex metabolic interplay among key organs that contribute to PHE dysregulation. These insights not only reinforce the importance of metabolic monitoring in HF management but also open avenues for therapeutic targets.