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Circulation Jun 2024Despite major advances in the clinical management of long QT syndrome, some patients are not fully protected by beta-blocker therapy. Mexiletine is a well-known sodium...
Therapeutic Efficacy of Mexiletine for Long QT Syndrome Type 2: Evidence From Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes, Transgenic Rabbits, and Patients.
BACKGROUND
Despite major advances in the clinical management of long QT syndrome, some patients are not fully protected by beta-blocker therapy. Mexiletine is a well-known sodium channel blocker, with proven efficacy in patients with sodium channel-mediated long QT syndrome type 3. Our aim was to evaluate the efficacy of mexiletine in long QT syndrome type 2 (LQT2) using cardiomyocytes derived from patient-specific human induced pluripotent stem cells, a transgenic LQT2 rabbit model, and patients with LQT2.
METHODS
Heart rate-corrected field potential duration, a surrogate for QTc, was measured in human induced pluripotent stem cells from 2 patients with LQT2 (KCNH2-p.A561V, KCNH2-p.R366X) before and after mexiletine using a multiwell multi-electrode array system. Action potential duration at 90% repolarization (APD) was evaluated in cardiomyocytes isolated from transgenic LQT2 rabbits (KCNH2-p.G628S) at baseline and after mexiletine application. Mexiletine was given to 96 patients with LQT2. Patients were defined as responders in the presence of a QTc shortening ≥40 ms. Antiarrhythmic efficacy of mexiletine was evaluated by a Poisson regression model.
RESULTS
After acute treatment with mexiletine, human induced pluripotent stem cells from both patients with LQT2 showed a significant shortening of heart rate-corrected field potential duration compared with dimethyl sulfoxide control. In cardiomyocytes isolated from LQT2 rabbits, acute mexiletine significantly shortened APD (∆APD shortening 113 ms), indicating a strong mexiletine-mediated shortening across different LQT2 model systems. Mexiletine was given to 96 patients with LQT2 either chronically (n=60) or after the acute oral drug test (n=36): 65% of the patients taking mexiletine only chronically and 75% of the patients who performed the acute oral test were responders. There was a significant correlation between basal QTc and ∆QTc during the test (= -0.8; <0.001). The oral drug test correctly predicted long-term effect in 93% of the patients. Mexiletine reduced the mean yearly event rate from 0.10 (95% CI, 0.07-0.14) to 0.04 (95% CI, 0.02-0.08), with an incidence rate ratio of 0.40 (95% CI, 0.16-0.84), reflecting a 60% reduction in the event rate (=0.01).
CONCLUSIONS
Mexiletine significantly shortens cardiac repolarization in LQT2 human induced pluripotent stem cells, in the LQT2 rabbit model, and in the majority of patients with LQT2. Furthermore, mexiletine showed antiarrhythmic efficacy. Mexiletine should therefore be considered a valid therapeutic option to be added to conventional therapies in higher-risk patients with LQT2.
PubMed: 38939955
DOI: 10.1161/CIRCULATIONAHA.124.068959 -
Circulation. Arrhythmia and... Jun 2024Atrial fibrillation (AF) events in cardiac implantable electronic devices (CIEDs) are temporally associated with stroke risk. This study explores temporal differences in...
BACKGROUND
Atrial fibrillation (AF) events in cardiac implantable electronic devices (CIEDs) are temporally associated with stroke risk. This study explores temporal differences in AF burden associated with HF hospitalization risk in patients with CIEDs.
METHODS
Patients with HF events from the Optum de-identified Electronic Health Records from 2007 to 2021 and 120 days of preceding CIED-derived rhythm data from a linked manufacturer's data warehouse were included. AF burden ≥5.5 h/d was defined as an AF event. The AF event burden in the case period (days 1-30 immediately before the HF event) was considered temporally associated with the HF event and compared with the AF event burden in a temporally dissociated control period (days 91-120 before the HF event). The odds ratio for temporally associated HF events and the odds ratio associated with poorly rate-controlled AF (>110 bpm) were calculated.
RESULTS
In total, 7257 HF events with prerequisite CIED data were included; 957 (13.2%) patients had AF events recorded only in either their case (763 [10.5%]) or control (194 [2.7%]) periods, but not both. The odds ratio for a temporally associated HF event was 3.93 (95% CI, 3.36-4.60). This was greater for an HF event with a longer stay of >3 days (odds ratio, 4.51 [95% CI, 3.57-5.68]). In patients with AF during both the control and case periods, poor AF rate control during the case period also increased HF event risk (1.78 [95% CI, 1.22-2.61]). In all, 222 of 4759 (5%) patients without AF events before their HF event had an AF event in the 10 days following.
CONCLUSIONS
In a large real-world population of patients with CIED devices, AF burden was associated with HF hospitalization risk in the subsequent 30 days. The risk is increased with AF and an uncontrolled ventricular rate. Our findings support AF monitoring in CIED algorithms to prevent HF admissions.
REGISTRATION
URL: https://www.clinicaltrials.gov; Unique identifier: NCT04452149 and NCT04987723.
PubMed: 38939945
DOI: 10.1161/CIRCEP.124.012842 -
Exploration (Beijing, China) Jun 2024Myocardial infarction (MI) is a leading cause of death worldwide. Few drugs hold the ability to depress cardiac electrical and structural remodeling simultaneously after...
Myocardial infarction (MI) is a leading cause of death worldwide. Few drugs hold the ability to depress cardiac electrical and structural remodeling simultaneously after MI, which is crucial for the treatment of MI. The aim of this study is to investigate an effective therapy to improve both electrical and structural remodeling of the heart caused by MI. Here, an "ion cocktail therapy" is proposed to simultaneously reverse cardiac structural and electrical remodeling post-MI in rats and minipigs by applying a unique combination of silicate, strontium (Sr) and copper (Cu) ions due to their specific regulatory effects on the behavior of the key cells involved in MI including angiogenesis of endothelial cells, M2 polarization of macrophages and apoptosis of cardiomyocyte. The results demonstrate that ion cocktail treatment attenuates structural remodeling post-MI by ameliorating infarct size, promoting angiogenesis in both peri-infarct and infarct areas. Meantime, to some extent, ion cocktail treatment reverses the deteriorative electrical remodeling by reducing the incidence rate of early/delayed afterdepolarizations and minimizing the heterogeneity of cardiac electrophysiology. This ion cocktail therapy reveals a new strategy to effectively treat MI with great clinical translation potential due to the high effectiveness and safety of the ion cocktail combination.
PubMed: 38939858
DOI: 10.1002/EXP.20230067 -
Acta Medica Philippina 2024Among pregnant women, 1-2% are anti-Ro positive and while half of them have symptoms of connective tissue disease, the rest are asymptomatic. The presence of anti-Ro is...
Among pregnant women, 1-2% are anti-Ro positive and while half of them have symptoms of connective tissue disease, the rest are asymptomatic. The presence of anti-Ro is of concern because of the risk of congenital heart block in the child. We report the case of an asymptomatic 27-year-old G2P1(1001) woman, who presented with persistent fetal bradycardia in her 21 week of gestation (AOG) and was found to have elevated titers for anti-Ro (>320 U/ml). Hydroxychloroquine 200 mg/day and prednisone 10 mg/day were given from the 33 week of gestation up until the delivery. At 37 weeks AOG, she delivered a live male neonate with a complete heart block. On the 6 day of life, the infant remained bradycardic, hence a pacemaker was inserted and heart rate maintained at 100-120 bpm. On subsequent follow-ups, the mother and child did not develop any systemic manifestations and the infant was thriving well. While a diseased condition may not be apparent in a pregnant anti-Ro positive woman, the risk of neonatal lupus (NL) is demonstrated in this patient's case. This report illustrates how prenatal care of an asymptomatic woman led to the discovery of a fetal abnormality and served to prepare the family and the medical team to ably handle the birth and subsequent care of a neonate with NL.
PubMed: 38939855
DOI: 10.47895/amp.vi0.6358 -
Frontiers in Pharmacology 2024Danhong injection (DHI) is widely used in the treatment of myocardial infarction (MI). We aimed to systematically review the efficacy and safety of DHI in a randomized...
OBJECTIVE
Danhong injection (DHI) is widely used in the treatment of myocardial infarction (MI). We aimed to systematically review the efficacy and safety of DHI in a randomized controlled experiment on MI.
METHODS
We searched the randomized controlled trials (RCTs) of DHI for MI published before 2 April 2023 in China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), Wanfang database, China Science and Technology Journal Database (VIP), PubMed, Web of Science, Cochrance Library, and Embase databases. The methodological quality of the included studies was evaluated using the Cochrane Handbook 5.3 criteria using the RevMan software, and meta-analysis was performed and a forest map was drawn.
RESULTS
A total of 38 trials included 3877 patients, including 2022 cases in the DHI treatment group and 1855 cases in the control group. Meta-analysis showed that the total effective rate (RR = 1.18%, 95% CI [1.14-1.12]) during treatment with DHI was higher than that of the control group. The prevalence of cardiac arrhythmia (RR = 0.55%, 95% CI [0.46-0.65]) was lower than that of the control group. The incidence of heart rate failure (RR = 0.45%, 95% CI [0.30-0.70]) was lower than that of the control group. The prevalence of cardiogenic shock (RR = 0.33%, 95% CI [0.11-1.04]) was > 0.05, and the difference was not statistically significant. There was no statistically significant difference in LVEF between the two groups (MD = 0.00%, 95% CI [0.00-0.00]). CK-MB (MD = -0.81%, 95% CI [-0.92∼ -0.69]) was lower than the control group. hs-CRP (MD = -1.09, 95% CI [-1.22∼ -0.97]) was lower than the control group. The incidence of adverse reactions (RR = 0.37, The 95% CI [0.17-0.82]) was lower than that in the control group.
CONCLUSION
Basing on our study, the use of DHI in the treatment of myocardial infarction patients is effective, can improve cardiac function, reduce the incidence of adverse reactions, and improve the overall quality of life.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023390973.
PubMed: 38939841
DOI: 10.3389/fphar.2024.1371959 -
Journal of Arrhythmia Jun 2024Implantable cardioverter-defibrillator (ICD) offers an opportunity to study inducibility of ventricular tachycardia (VT) or ventricular fibrillation (VF) by performing...
BACKGROUND
Implantable cardioverter-defibrillator (ICD) offers an opportunity to study inducibility of ventricular tachycardia (VT) or ventricular fibrillation (VF) by performing noninvasive programmed ventricular stimulation (NIPS). Whether NIPS can predict future arrhythmic events or mortality in patients with primary prevention ICD, has not yet been examined.
METHODS
From the NIPS-ICD study (ClinicalTrials ID: NCT02373306) 41 consecutive patients (34 males, age 64 ± 11 years, 76% ischemic cardiomyopathy [ICM]) had ICD for primary prevention indication. Patients underwent NIPS using a standardized protocol of up to three premature extrastimuli at 600, 500 and 400 ms drive cycle lengths. NIPS was classified as positive if sustained VT or VF was induced. The study endpoint was occurrence of sustained VT/VF during the follow-up.
RESULTS
At baseline NIPS, VT/VF was induced in 8 (20%) ICM patients. During the 5-year follow-up, the VT/VF occurred in 7 (17%) patients, all with ICM. The difference between NIPS-inducible versus NIPS-noninducible patients regarding VT/VF occurrence did not meet statistical significance (38% vs. 12%, log rank test = .11). After a 5-year follow-up, the mortality rate was significantly higher in patients who had VT/VF induced at NIPS versus no VT/VF at NIPS (38% vs. 12%, = .043). The occurrence of a composite endpoint consisting of VT/VF recurrence or death in patients with ICM was also most frequent in the NIPS-inducible group (75% vs. 35%, = .037).
CONCLUSIONS
Inducibility of VT/VF during NIPS in ICM patients with primary prevention ICD is associated with higher mortality and higher incidence of composite endpoint consisting of death or VT/VF during a long-term observation.
PubMed: 38939799
DOI: 10.1002/joa3.13017 -
Journal of Arrhythmia Jun 2024The relationships between frailty and clinical outcomes in elderly Japanese patients with non-valvular atrial fibrillation (NVAF) after catheter ablation (CA) have not...
BACKGROUND
The relationships between frailty and clinical outcomes in elderly Japanese patients with non-valvular atrial fibrillation (NVAF) after catheter ablation (CA) have not been established. We evaluated the frailty rate of patients undergoing CA for NVAF, examined whether CA for NVAF improves frailty, and analyzed the CA outcomes of patients with and without frailty.
METHODS
Elderly Japanese patients (≥65 years; mean age: 72.8 years) who participated in the real-world ablation therapy with anti-coagulants in management of atrial fibrillation registry and who responded to the frailty screening index survey were included ( = 213). Frailty and AF recurrence were assessed preoperatively and at 3 and 6 months after CA.
RESULTS
Twenty-six patients (12.8%) were frail, 109 (53.7%) were pre-frail, and 68 (33.5%) were robust. Cardiovascular (frailty: 0.5%/person-year; pre-frailty: 0.1%/person-year; robust: 0.1%/person-year) and cardiac (frailty: 0.5%/person-year; pre-frailty: 0.1%/person-year; robust: 0.1%/person-year) events, as well as major bleeding (frailty: 0.3%/person-year; pre-frailty: 0.1%/person-year; robust: 0.1%/person-year), were numerically more frequent in the frailty group. No deaths from cardiovascular or stroke/systemic thromboembolic events occurred. A large proportion of patients did not experience 3-month (frailty: 96.2%; pre-frailty: 96.3%; robust: 88.2%) or 6-month (frailty: 88.5%; pre-frailty: 91.7%; robust: 86.8%) AF recurrence after CA. Weight loss, walking speed, and fatigue improved in the frailty and pre-frailty groups after CA.
CONCLUSION
Japanese patients aged ≥65 years with frailty or pre-frailty had improved frailty screening index components, such as weight loss, walking speed and fatigue, after CA. Therefore, elderly patients with frailty or pre-frailty may benefit from CA for NVAF.
PubMed: 38939797
DOI: 10.1002/joa3.13038 -
Journal of Arrhythmia Jun 2024Despite the positive impact of implantable cardioverter defibrillators (ICDs) and wearable cardioverter defibrillators (WCDs) on prognosis, their implantation is often...
Multicenter prospective observational study to clarify the current status and clinical outcome in Japanese patients who have an indication for implantable cardioverter defibrillator (ICD) or wearable cardioverter defibrillator (WCD) (TRANSITION JAPAN-ICD/WCD study): Rationale and design of a...
BACKGROUND
Despite the positive impact of implantable cardioverter defibrillators (ICDs) and wearable cardioverter defibrillators (WCDs) on prognosis, their implantation is often withheld especially in Japanese heart failure patients with reduced left ventricular ejection fraction (HFrEF) who have not experienced ventricular tachycardia (VT) or ventricular fibrillation (VF) for uncertain reasons. Recent advancements in heart failure (HF) medications have significantly improved the prognosis for HFrEF. Given this context, a critical reassessment of the treatment and prognosis of ICDs and WCDs is essential, as it has the potential to reshape awareness and treatment strategies for these patients.
METHODS
We are initiating a prospective multicenter observational study for HFrEF patients eligible for ICD in primary and secondary prevention, and WCD, regardless of device use, including all consenting patients. Study subjects are to be enrolled from 31 participant hospitals located throughout Japan from April 1, 2023, to December 31, 2024, and each will be followed up for 1 year or more. The planned sample size is 651 cases. The primary endpoint is the rate of cardiac implantable electronic device implementation. Other endpoints include the incidence of VT/VF and sudden death, all-cause mortality, and HF hospitalization, other events. We will collect clinical background information plus each patient's symptoms, Clinical Frailty Scale score, laboratory test results, echocardiographic and electrocardiographic parameters, and serial changes will also be secondary endpoints.
RESULTS
Not applicable.
CONCLUSION
This study offers invaluable insights into understanding the role of ICD/WCD in Japanese HF patients in the new era of HF medication.
PubMed: 38939793
DOI: 10.1002/joa3.13028 -
Journal of Arrhythmia Jun 2024A 26-year-old man with long QT syndrome (LQTS) underwent subcutaneous implantable cardioverter-defibrillator (S-ICD) implantation. The patient exhibited sinus...
A 26-year-old man with long QT syndrome (LQTS) underwent subcutaneous implantable cardioverter-defibrillator (S-ICD) implantation. The patient exhibited sinus bradycardia relative to his age. The heart rate decreased, and the QT interval became longer with the administration of β-blockers, the first-line therapy for LQTS. The patient experienced frequent S-ICD discharges. Subsequently, a single-chamber pacemaker was implanted, and the 12-lead electrocardiogram showed atrial pacing and ventricular sensing at 60 beats per minute with a shorter QTc interval. After converting to "double-device therapy," the patient did not experience any ventricular arrhythmia events.
PubMed: 38939789
DOI: 10.1002/joa3.13027 -
Journal of Arrhythmia Jun 2024Hypertrophic cardiomyopathy (HCM) is frequently associated with atrial fibrillation (AF). We compared clinical, echocardiographic, and electrophysiological parameters...
BACKGROUND
Hypertrophic cardiomyopathy (HCM) is frequently associated with atrial fibrillation (AF). We compared clinical, echocardiographic, and electrophysiological parameters between HCM subtypes and those without HCM at AF catheter ablation (AFCA) and analyzed post-AFCA reverse remodeling and AF recurrence based on HCM presence and subtype.
METHODS
Among 5161 consecutive patients who underwent de novo AFCA, we included HCM patients and control patients who were age-, gender-, and AF type-matched. Between AF-HCM patients and controls, we compared baseline values for left atrium (LA) wall thickness (LAWT), reverse remodeling at 1-year follow-up, and procedural outcomes over the course of follow-up between two groups.
RESULTS
A total of 122 AF-HCM patients and 318 control patients were included. AF-HCM patients had more frequent heart failure and higher LA diameter, E/Em, and LA pressure (all, < .001). However, LAWT did not differ from control group. A year after AFCA, degree of LA reverse remodeling was significantly lower in AF-HCM than in control group (ΔLA dimension, = .025). Nonapical HCM (HR 1.71; 95% CI 1.05-2.80), persistent AF (HR 1.46; 95% CI 1.05-2.04), and LA dimension (HR 1.04; 95% CI 1.01-1.06) were independent risk factors for AF recurrence. During 78.0 months of follow-up, nonapical HCM patients showed higher AF recurrence rate than both apical HCM (log-rank = .005) and control patients (log-rank = .002).
CONCLUSIONS
The presence of HCM, particularly nonapical HCM, displayed increased LA hemodynamic loading with diastolic dysfunction and had poorer rhythm outcomes after AFCA compared to both apical HCM and control group.
PubMed: 38939784
DOI: 10.1002/joa3.13061