Cardiac Conduction Block Research Articles

The Combination of Hyperuricemia and Elevated High-Sensitivity C-Reactive Protein Increased the Risk of Cardiac Conduction Block.

This study aimed to explore the impact of a combination of hyperuricemia (HUA) and excessive high-sensitivity C-reactive protein (hs-CRP) levels on the likelihood of developing cardiac conduction block (CCB). Additionally, it sought to assess whether the influence of uric acid (UA) on CCB is mediated by hs-CRP. A prospective study was executed utilizing data from the Kailuan cohort, including 81,896 individuals initially free from CCB. The participants were categorized into four groups depending on the existence of HUA and low-grade inflammation (hs-CRP>3 mg/L). Cox regression analysis was employed to ascertain hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of incident CCB. A mediation analysis was performed to determine if hs-CRP functioned as a mediator in the connection between UA levels and the incidence of CCB. During a median observation period of 11.8 years, we identified 3160 cases of newly occurring CCB. Compared with the low UA/low CRP group, the combination of HUA and low-grade inflammation elevated the CCB risks (HR:1.56, 95% CI:1.22-1.99), atrioventricular block (AVB) (HR:1.88, 95% CI:1.27-2.77), and right bundle branch block (HR:1.47, 95% CI:1.02-2.12), respectively. Mediation analysis revealed that in the HUA group, compared with the non-HUA group, the risk of CCB elevated by 14.0%, with 10.3% of the increase mediated through hs-CRP. HUA combined with elevated hs-CRP increasedthe risk of CCB, especially AVB. The connection between UA and the CCB risk was partly mediated by hs-CRP.

The Value of the Electrocardiogram in Adult Congenital Heart Disease.

The electrocardiogram is the first test that is undertaken when evaluating a patient's heart. Diagnosing congenital heart disease in an adult (ACHD) can be facilitated by knowing the classical electrocardiographic (EKG) findings. These EKG findings often result from the congenital defect that prevents a part of the cardiac conduction system from occupying its normal anatomic position. When these classical EKG findings are not present, the clinician should consider alternate diagnoses. As the patient with congenital heart disease ages, with native anatomy or after surgical or device repair, the EKG can be used to assess the patient's status and to decide if and when treatment requires adjustment. This is because the electrocardiogram (EKG) can diagnose the hypertrophy or enlargement in a cardiac chamber that results from the congenital defect or anomaly and can diagnose an arrhythmia that might compromise an otherwise stable anatomy. While ACHD often involves intracardiac shunting, in many cases the abnormality only involves cardiac electrical conduction block or ventricular repolarization. These life-threatening diseases can be diagnosed with an EKG. This review will demonstrate and explain how the EKG can be used to diagnose and follow adults with congenital heart disease. When coupled with history and physical examination, the value of the EKG in ACHD will be apparent. A diagnosis can then be made or a differential diagnosis proposed, before an imaging study is ordered.

Distinct uric acid trajectories are associated with incident cardiac conduction block

BackgroundThe association of longitudinal uric acid (UA) changes with cardiac conduction block risk is unclear. We aimed to identify the trajectories of UA and explore its association with cardiac conduction block.MethodsA total of 67,095 participants with a mean age of 53.12 years were included from the Kailuan cohort in Tangshan, China, who were free of cardiac conduction block and with repeated measurements of UA from 2006 to 2012. UA trajectories during 2006 to 2012 were identified by group-based trajectory modeling. Cox proportional hazard regression models were used to assess the association of UA trajectories with cardiac conduction block.ResultsWe categorized three observed discrete trajectories of UA during 2006–2012 period: low-stable, moderate-stable, and high-stable. Over a median follow-up of 6.19 years, we identified 1405 (2.09%) incident cardiac conduction block. Compared to those in the low-stable trajectory, the adjusted hazard ratios (HRs) (95% confidence interval [CI]) of cardiac conduction block in the moderate-stable and high-stable trajectory were 1.30 (1.16–1.47) and 1.86 (1.56–2.22), and HRs of atrioventricular block were 1.39 (1.12–1.72) and 2.90 (2.19–3.83), and HRs of bundle branch blocks were 1.27 (1.10–1.47) and 1.43 (1.13–1.79). Notably, although the average UA level in the moderate-stable UA trajectory group is within the normal range, the risk of cardiac conduction block has increased.ConclusionsThe moderate-stable and high-stable trajectories are associated with increased risk for new-onset cardiac conduction block. Monitoring UA trajectories may assist in identifying subpopulations at higher risk for cardiac conduction block.

Association between cardiac conduction block and cardiovascular disease and all-cause mortality: The kailuan study

BackgroundAlthough bundle branch block and atrioventricular block are recognized to be association with cardiovascular disease (CVD) and mortality, the relationship between cardiac conduction block (CCB) and both CVD and all-cause mortality has yet to be explored. AimsTo explore the relationship between CCB and CVD and all-cause mortality. Methods and resultsWe included 145,805 subjects (mean age 49.7 years, 81.2% males) from the kailuan study. CCB was diagnosed through a 12‑lead electrocardiograph (ECG). Mortality and CVD events were ascertained through multiple sources, including a municipal social insurance institution, hospital records, death certificates, and regular active follow-ups. After a mean follow-up of 12.5 years, 18,301 cases developed all-cause mortality. After excluding 4443 subjects with CVD presence at baseline, 13,208 cases of CVD occurred among the 141,362 study subjects during follow-up. Compared with non-CCB group, the cumulative incidence of CVD and all-cause mortality for CCB group was 18.38% VS 12.14% and 33.45% VS 14.18%, respectively. The multivariable-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) with CCB group were 1.25(1.17–1.34) for CVD, and 1.31(1.25–1.38) for all-cause mortality. Additionally, there were generally stronger associations for CCB with all-cause mortality and CVD in younger participants compared with their older counterparts (Ps-interaction <0.001). ConclusionCCB can increase the risk of CVD and all-cause mortality in the general population. Our findings highlight the importance of strategies for preventing CCB to reduce the risk of CVD and mortality.

Obesity and Cardiac Conduction Block Disease in China

Although a high body mass index (BMI) has been found to be associated with increased risk of cardiac conduction block (CCB) in older adults, no further studies have investigated the association between obesity and CCB in the general population. To investigate the association between obesity and CCB, including its subtypes. This cohort study used data from participants in the Kailuan Study in China (2006-2018) who had completed a physical examination in 2006 (baseline) and had not experienced CCB before baseline. Data analysis was conducted from March to September 2023. Obesity status was defined by BMI in 3 groups: normal weight (18.5 to <24), overweight (24 to <28), and obesity (≥28). The primary outcome was CCB, which was diagnosed from standard 12-lead electrocardiography. The primary end point included high-grade atrioventricular block (HAVB), complete right bundle branch block, complete left bundle branch block, left anterior fascicular block (LAFB), and left posterior fascicular block. First-degree atrioventricular block (FAVB), second-degree type 1 AVB, HAVB, complete and incomplete right and left bundle branch block, LAFB, and left posterior fascicular block were considered separately as secondary end points. Among 86 635 participants (mean [SD] age, 50.8 [11.9] years; 68 205 males [78.7%]), there were 33 259 individuals with normal weight (38.4%), 37 069 individuals with overweight (42.8%), and 16 307 individuals with obesity (18.8%). The mean (SD) follow-up was 10.6 (3.07) years. In the multivariable Cox proportional hazards regression analysis, obesity was associated with an increased risk of incident CCB (hazard ratio [HR], 1.21; 95% CI, 1.04-1.42) vs normal BMI. In secondary analysis, obesity was associated with an increased risk of FAVB (HR, 1.44; 95% CI, 1.21-1.73), HAVB (HR, 1.99; 95% CI, 1.03-3.82), and LAFB (HR, 1.29; 95% CI, 1.03-1.62) vs normal BMI. There was no association between obesity and other CCB subtypes. Obesity was associated with a greater increase in risk of CCB vs normal BMI in older (aged ≥65 years; HR, 1.44; 95% CI, 1.05-1.96) vs younger (aged <65 years; HR, 1.13; 95% CI, 0.96-1.34) participants (P for interaction < .001) and those with diabetes (HR, 2.16; 95% CI, 1.24-3.76) vs without diabetes (HR, 1.19; 95% CI, 1.02-1.39) (P for interaction = .02). This study found that obesity was associated with an increased risk of CCB, with greater increases in risk for FAVB, HAVB, and LAFB. Individuals who were older and those who had diabetes had larger increases in risk.

Potential cardioprotective effects of acetylcholinesterase inhibitors in patients with Alzheimer's disease

Abstract Background In patients with mild to moderate Alzheimer's disease (AD), acetylcholinesterase inhibitors (AChE-I) are commonly employed to improve cognitive function. They increase the amount of acetylcholine (ACh) in the neuronal synapses, but bradycardia, cardiac electrical conduction blocks and hypotension due to muscarinic M2 receptor stimulation are potential side effects. However, whether these "side effects" could play a potential protective effect on cardiovascular (CV) events is not yet well defined. Purpuses To evaluate potential beneficial cardiac effects of AChE-Is in patients with AD, in terms of reduction of major adverse cardiovascular events (MACEs). Methods We conducted a retrospective, monocentric, observational cohort study in patients referred to our hospital. Two groups were considered: the interventional group included AD patients treated with AChE-I. The control group enrolled a cohort of subjects matched for age and comorbidities, recruited between caregivers of intervention group subjects that were cognitively unimpaired and not taking AchE-I. The primary endpoint was a composite of hospitalization for heart failure (HF), non-fatal acute myocardial infarction (AMI), myocardial revascularization, hospitalization for cardiovascular (CV) causes, cardiovascular mortality and occurrence of stroke and/or TIA during total 5 year follow-up period (MACEs). Secondary endpoints were each individual component of the primary end point, total deaths, non-cardiovascular death and incidence of pacemaker implant. Results 221 AD patients treated with AChE-I (91 with Donepezil, 130 with Rivastigmine) were included in intervention group and 221 non-AD patients in control group. Groups were homogeneous in terms of age, gender and main cardiovascular risk factors, except for family history of cardiovascular diseases (CVD), which was more frequent in control group. During a median follow-up of 3.1 years the primary endpoint occurred in 24 patients in intervention group (2.1 per 100 patient-years) compared to 56 patients in the control group (5.0 per 100 patient-years). Therefore, AChE-I therapy resulted a protective factor from primary endpoint (HR 0.48, 95% CI 0.24-0.95; p= 0.036). Even not significant, the difference was mainly driven by myocardial revascularization (3.2% in intervention group vs 6.8% in controls) and hospitalization for heart failure (4.5% in intervention group vs 14.5% in controls). Non-CVD mortality was significantly higher in treatment group (13,6% in intervention group vs 2,7% in controls). No significant difference was observed between groups in terms of other secondary outcomes. Conclusions Among patients with AD, use of AChE-I may be protective for CV outcomes, especially reducing HF hospitalisation and myocardial revascularization.Kaplan-Meier of cumulative MACEsNumber of Event/Years

U-Shaped Association Between Monocyte-Lymphocyte Ratio and Risk of Cardiac Conduction Block.

Inflammation plays a critical role in the development of cardiac conduction block (CCB), which is associated with an increased risk of morbidity and mortality. The monocyte-lymphocyte ratio (MLR) acts as a novel inflammatory marker; however, its association with CCB has not yet been studied. This study aimed to investigate the association between MLR and CCB risk. In total, 82,472 CCB-free participants were identified from the Kailuan study. MLR was calculated using the monocyte count/lymphocyte count. The participants were stratified based on quartiles of MLR levels. Incident CCB and its subtypes were ascertained from electrocardiograms at biennial follow-up visits. The Cox proportional hazards model and restricted cubic spline analysis were used to investigate the association between MLR with CCB and its subtypes. During a median follow-up of 10.4 years, 3222 incident CCB cases were observed. A U-shaped association was observed between MLR and CCB risk (Pnonlinearity <0.05). After multivariate adjustment, individuals in the highest MLR quartile had a hazard ratio (HR) of 1.212 (95% CI: 1.097-1.340; Q4 vs Q2), while those in the lowest MLR quartile had an HR of 1.106 (95% CI: 1.000-1.224; Q1 vs Q2). Sensitivity and subgroup analyses yielded consistent results. The U-shaped association persisted for atrioventricular block (AVB) in subtype analyses. MLR was significantly associated with an increased risk of new-onset CCB. Assessing MLR may have clinical relevance for predicting CCB risk, providing valuable insights for preventive strategies and patient management. The pre-registered clinical trial number is ChiCTR-TNC-11001489.

Predictors of permanent pacemaker implantation in aortic valve diseases after TAVI with vitaFlow liberty system.

Permanent pacemaker implantation (PPI) is a known complication in patients with aortic stenosis following transcatheter aortic valve implantation (TAVI). However, there is limited research on TAVI for pure aortic regurgitation (PAR), and more investigation is needed to determine the occurrence of postoperative cardiac conduction block and the need for PPI in this population. Therefore, this retrospective analysis aimed to evaluate the incidence of cardiac conduction block and the necessity of PPI after TAVI in patients with different types of aortic valve disease, including pure aortic stenosis (PAS), aortic stenosis with regurgitation (ASR), and PAR. Clinical data of 100 patients who TAVI were analyzed retrospectively. The incidence of conduction block was assessed, and clinical factors were examined to predict the necessity of PPI. Cardiac conduction block was found to be a common complication following TAVI, particularly in patients with PAR. PAR was identified as an independent risk factor for requiring PPI. Additionally, first-degree atrioventricular block emerged as a sensitive predictor for PPI in patients with PAR. These findings provide valuable insights into the safety and effectiveness of TAVI, which can help enhance patient management and reduce complications.

Effectiveness and Safety of Transcatheter Closure of Various Ventricular Septal Defects Using Second-Generation Amplatzer Duct Occluders

Objective: This study was designed to determine the long-term safety and efficacy of using the Amplatzer Duct Occluder II (ADO II) for the closure of various ventricular septal defects (VSDs). Methods: From January 2011 to December 2019, selected VSD patients were treated through transcatheter intervention using ADO II occluders. The closure results and complications from 188 patients, involving 167 perimembranous ventricular septal defects (pmVSDs), 9 intracristal VSDs, 11 post surgery residual shunts and 1 post closure residual shunt with the mean outlet diameter3.1 ± 0.8 mm under angiography, were enrolled in this study. Results: The success rate was 98.9% for all procedures. During the median 77-month follow-up period, no cases of complete atrioventricular block (cAVB), infective endocarditis or death occurred. One major adverse event (0.5%) was recorded: cerebrovascular accident occurred 1 day after the procedure in one patient who was transferred to the neurology department. The residual shunt rate was 44.6%, which was the most common minor adverse event. The cardiac conduction block rate was 4.3%. Specifically, one pmVSD patient developed intermittent LBBB during the 28-month follow-up. There were 3 patients (1.6%) with new-onset mild tricuspid insufficiency, and the insufficiency degree was stable during follow-up. There was no new-onset aortic insufficiency that occurred. Conclusions: Transcatheter closure of pmVSDs, some intracristal VSDs, some postsurgery or postclosure residual shunts using ADO II occluders were both safe and effective and yielded excellent long-term results in selected patients.

Enhanced sodium channel inactivation by temperature and FHF2 deficiency blocks heat nociception.

Transient voltage-gated sodium currents are essential for the initiation and conduction of action potentials in neurons and cardiomyocytes. The amplitude and duration of sodium currents are tuned by intracellular fibroblast growth factor homologous factors (FHFs/iFGFs) that associate with the cytoplasmic tails of voltage-gated sodium channels (Na v s), and genetic ablation of Fhf genes disturbs neurological and cardiac functions. Among reported phenotypes, Fhf2null mice undergo lethal hyperthermia-induced cardiac conduction block attributable to the combined effects of FHF2 deficiency and elevated temperature on the cardiac sodium channel (Na v 1.5) inactivation rate. Fhf2null mice also display a lack of heat nociception, while retaining other somatosensory capabilities. Here, we use electrophysiological and computational methods to show that the heat nociception deficit can be explained by the combined effects of elevated temperature and FHF2 deficiency on the fast inactivation gating of Na v 1.7 and tetrodotoxin-resistant sodium channels expressed in dorsal root ganglion C fibers. Hence, neurological and cardiac heat-associated deficits in Fhf2null mice derive from shared impacts of FHF deficiency and temperature towards Na v inactivation gating kinetics in distinct tissues.

Analysis of clinically-reported, memantine-induced cardiovascular adverse responses using the halothane-anesthetized dogs: Reverse translational study

Although NMDA receptor antagonist memantine is considered to be better tolerated than cholinesterase inhibitors on treating Alzheimer's disease, several types of cardiovascular adverse events have been associated with memantine treatment, including hypertension, myocardial infarction, severe bradycardia and QT-interval prolongation. In order to clarify how memantine induces these cardiovascular adverse events, we assessed its electropharmacological effects using the halothane-anesthetized dogs (n = 4). Memantine hydrochloride was intravenously administered in doses of 0.01, 0.1 and 1 mg/kg over 10 min, providing subtherapeutic, clinically-relevant and supratherapeutic concentrations, respectively. The low to high doses increased the mean blood pressure and left ventricular contraction and enhanced the atrioventricular nodal conduction, suggesting an increase of sympathicotonic output from the central nervous system similarly to donepezil, which might induce myocardial ischemia in patients with coronary artery disease. Meanwhile, the high dose suppressed the intra-atrial conduction and the low to high doses inhibited the intra-ventricular conduction, indicating potential to induce severe bradycardic adverse event by advanced cardiac conduction block in susceptible patients. Memantine alone did not induce repolarization delay, indicating lack of risk for inducing torsade de pointes. Thus, these in vivo experimental findings may provide basic information to better understand the clinically observed adverse events of memantine.

NONMMUT140591.1 may serve as a ceRNA to regulate Gata5 in UT-B knockout-induced cardiac conduction block.

We intended to explore the potential molecular mechanisms underlying the cardiac conduction block inducted by urea transporter (UT)-B deletion at the transcriptome level. The heart tissues were harvested from UT-B null mice and age-matched wild-type mice for lncRNA sequencing analysis. Based on the sequencing data, the differentially expressed mRNAs (DEMs) and lncRNAs (DELs) between UT-B knockout and control groups were identified, followed by function analysis and mRNA–lncRNA co-expression analysis. The miRNAs were predicted, and then the competing endogenous RNA (ceRNA) network was constructed. UT-B deletion results in the aberrant expression of 588 lncRNAs and 194 mRNAs. These DEMs were significantly enriched in the inflammation-related pathway. A lncRNA–mRNA co-expression network and a ceRNA network were constructed on the basis of the DEMs and DELs. The complement 7 (C7)–NONMMUT137216.1 co-expression pair had the highest correlation coefficient in the co-expression network. NONMMUT140591.1 had the highest degree in the ceRNA network and was involved in the ceRNA of NONMMUT140591.1-mmu-miR-298-5p-Gata5 (GATA binding protein 5). UT-B deletion may promote cardiac conduction block via inflammatory process. The ceRNA NONMMUT140591.1-mmu-miR-298-5p-Gata5 may be a potential molecular mechanism of UT-B knockout-induced cardiac conduction block.

A newly identified missense mutation in CLCA2 is associated with autosomal dominant cardiac conduction block

BackgroundProgressive cardiac conduction defect (PCCD), also known as Lenegre-Lev disease, is one of the most common heart conduction abnormalities. Previous studies have screened for known mutation sites that cause heart block in a 68-person family with a history of PCCD, revealed no mutations. ObjectiveTo screen pathogenic genes of the PCCD family and to study the function of the gene mutations related to heart block diseases. MethodsWhole exome sequencing (WES) was performed on two PCCD patients and one non-PCCD family member to find the related pathogenic gene. After family co-segregation and preliminary functional analysis, we identified the mutant gene CLCA2. To study the function of this gene, we constructed mutant-gene mice using CRISPR-Cas9 technology, and electrocardiogram monitoring was performed after genotype verification. ResultsThe CLCA2 c.G1725T mutation was identified and co-segregated with the phenotype. The analysis showed that the CLCA2 c.G1725T mutation is harmful and mainly affects protein glycosylation. Immunofluorescence staining revealed that CLCA2 was highly expressed in the sinoatrial node (SAN) tissues. Electrocardiogram monitoring of the mice revealed that CLCA2 point mutations induced mild conduction block and ectopic pacemakers. ConclusionOur findings indicate that a novel heterozygous missense mutation c.G1725T of the CLCA2 gene may be associated with heart block disease and the mutation in this gene may lead to sinus node lesions and conduction blocking.

The acute toxic effects of platinum nanoparticles on ion channels, transmembrane potentials of cardiomyocytes in vitro and heart rhythm in vivo in mice.

BackgroundPlatinum nanoparticles (PtNPs) have been considered a nontoxic nanomaterial and been clinically used in cancer chemotherapy. PtNPs can also be vehicle exhausts and environmental pollutants. These situations increase the possibility of human exposure to PtNPs. However, the potential biotoxicities of PtNPs including that on cardiac electrophysiology have been poorly understood.MethodsIon channel currents of cardiomyocytes were recorded by patch clamp. Heart rhythm was monitored by electrocardiogram recording. Morphology and characteristics of PtNPs were examined by transmission electron microscopy, dynamic light scattering and electrophoretic light scattering analyses.ResultsIn cultured neonatal mice ventricular cardiomyocytes, PtNPs with diameters 5 nm (PtNP-5) and 70 nm (PtNP-70) concentration-dependently (10–9 – 10–5 g/mL) depolarized the resting potentials, suppressed the depolarization of action potentials and delayed the repolarization of action potentials. At the ion channel level, PtNPs decreased the current densities of INa, IK1 and Ito channels, but did not affect the channel activity kinetics. In vivo, PtNP-5 and PtNP-70 dose-dependently (3–10 mg/kg, i.v.) decreased the heart rate and induced complete atrioventricular conduction block (AVB) at higher doses. Both PtNP-5 and PtNP-70 (10–9 – 10–5 g/mL) did not significantly increase the generation of ROS and leak of lactate dehydrogenase (LDH) from cardiomyocytes within 5 mins after exposure except that only very high PtNP-5 (10–5 g/mL) slightly increased LDH leak. The internalization of PtNP-5 and PtNP-70 did not occur within 5 mins but occurred 1 hr after exposure.ConclusionPtNP-5 and PtNP-70 have similar acute toxic effects on cardiac electrophysiology and can induce threatening cardiac conduction block. These acute electrophysiological toxicities of PtNPs are most likely caused by a nanoscale interference of PtNPs on ion channels at the extracellular side, rather than by oxidative damage or other slower biological processes.

Familial Clustering of Cardiac Conduction Defects and Pacemaker Insertion

The etiopathogenesis of electrocardiographic bundle branch and atrioventricular blocks is not fully understood. We investigated familial clustering of cardiac conduction defects and pacemaker insertion in the FHS (Framingham Heart Study). Additionally, we assessed familial clustering of pacemaker insertion in the Danish general population. In FHS, we used multivariable-adjusted logistic regression models to investigate the association of parental atrioventricular block (PR interval, ≥0.2 s), complete bundle branch block (QRS, ≥0.12 s), or pacemaker insertion with the occurrence of cardiac conduction abnormalities in their offspring. The Danish nationwide administrative registries were interrogated to assess the relations of parental pacemaker insertion with offspring pacemaker insertion. In FHS (n=371 cases with first-degree atrioventricular block, complete bundle branch block, or pacemaker insertion, and 1471 age- and sex-matched controls), individuals with at least 1 affected parent with a conduction defect had a 1.65-fold odds (odds ratio, 95% CI, 1.32-2.07) for manifesting an atrioventricular block and a 1.62-fold odds (95% CI, 1.08-2.42) for developing a complete bundle branch block. If at least 1 parent had any electrocardiographic conduction defect or pacemaker insertion, the offspring had a 1.62-fold odds (95% CI, 1.31-2.00) for experiencing any of these conditions. In Denmark (n=2 824 199 individuals; 5397 incident pacemaker implantations), individuals with at least 1 first-degree relative with history of pacemaker insertion had a multivariable-adjusted 1.68-fold (incidence rate ratio, 95% CI, 1.49-1.89) risk of undergoing a pacemaker insertion. If the affected relative was ≤45 years of age, the incidence rate ratio was markedly increased to 51.0 (95% CI, 32.7-79.9). Cardiac conduction blocks and risk for pacemaker insertion cluster within families. A family history of conduction system disturbance or pacemaker insertion should trigger increased awareness of a similar propensity in other family members, especially so when the conduction system disease occurs at a younger age.

Differences associated with age at onset in early systemic sclerosis patients: a report from the EULAR Scleroderma Trials and Research Group (EUSTAR) database

Objective: The aim of this study was to analyse differences in clinical presentation in patients with early (< 3 years’ duration) systemic sclerosis (SSc), comparing three age groups according to disease subsets.Method: Cross-sectional analysis of the prospective EULAR Scleroderma Trials and Research database (EUSTAR) was performed. Patients fulfilling preliminary American College of Rheumatology 1980 classification criteria for SSc, with < 3 years from the first non-Raynaud’s SSc symptom at first entry, were selected. Patients with < 3 years from the first SSc symptom, including Raynaud’s phenomenon, were also analysed. SSc-related variables, including antibodies, SSc subsets, and organ involvement, were examined. Age was categorized into ≤ 30, 31–59, and ≥ 60 years. We performed descriptive and bivariate analyses.Results: The study included 1027 patients: 90% Caucasian, 80% women, and 40% with diffuse disease. In early stages of SSc, younger patients had significantly more anti-Scl-70 antibodies and diffuse disease. With increasing age, we observed more elevation of estimated pulmonary systolic pressure on echocardiography (5%, 13%, and 30%, respectively, in the three age groups), cardiac conduction blocks (6%, 6%, and 15%), and left ventricular diastolic dysfunction (4%, 12%, and 27%). The results were similar for 650 patients with < 3 years from first SSc symptom, including Raynaud’s.Conclusion: In early stages of SSc, older patients showed data indicating more severe disease with greater cardiac involvement. The diffuse subset was more frequent in the younger subgroup. The identification of such differences may help in selecting appropriate management for individual patients in clinical practice.

Aberrant Deactivation-Induced Gain of Function in TRPM4 Mutant Is Associated with Human Cardiac Conduction Block

A gain-of-function mutation in the Ca2+-activated transient receptor potential melastatin member 4 (TRPM4A432T) is linked to life-threatening cardiac conduction disturbance, but the underlying mechanism is unclear. For deeper insights, we used photolysis of caged Ca2+, quantitative Ca2+, and electrophysiological measurements. TRPM4A432T's 2-fold larger membrane current was associated with 50% decreased plasma membrane expression. Kinetic analysis unveiled 4-fold slower deactivation that was responsible for the augmented membrane current progressively rising during repetitive human cardiac action potentials. Rational mutagenesis of TRPM4 at position 432 revealed that the bulkiness of the amino acid was key to TRPM4A432T's aberrant gating. Charged amino acids rendered the channel non-functional. The slow deactivation caused by an amino acid substitution at position 432 from alanine to the bulkier threonine represents a key contributor to the gain of function in TRPM4A432T. Thus, our results add a mechanism in the etiology of TRP channel-linked human cardiac channelopathies.

Integrated approach in bridging the gap betweenBiomedicine - A reductionistic science and Ayurveda- A holistic science

Reductionism and Holism are the two prevailing thoughts in science even so in medical science. Both pose to have different set of prorsquos and conrsquos. This lead to need for integration of the two streams of thoughts and emergence of Integrated Approach. In many of the situations Integration has helped the medical community to understand the Holistic concepts in a better way. But somewhere it is also true that Integration has led to some misinterpretations. In an attempt to integrate two sciences the basic principles of holistic sciences are sometimes violated or neglected from consideration. Thus there is need to channel this process of integration. Here is an attempt to illustrate the Integration of Ayurveda and Biomedicine Contemporary science. The clinical condition Peripheral Vascular Disorder is integrated with Vatarakta Classical description of clinical condition Sanyaasa is integrated with Stroke Adams Syndrome a Cardiac Conduction Block. Following the Integrated approach a brief insight into the possible Chikitsa Siddhanta for Peripheral Vascular Disorder and Cardiac Conduction Blocks are outlined.nbsp

A novel de nova missense LMNA mutation in a Turkish patient with laminopathies

The laminopathies associated to the lamin A/C (LMNA) gene mutations at chromosome 1q22 region; comprise different well-characterized phenotypes. Some of the multi-systemic laminopathies are lipodystrophy, Charcot-Marie Tooth disease (CMT), Emery-Dreifuss muscular dystrophy (EDMD) and Limb Girdle muscular dystrophy 1B (LGMD1B). The LGMD1B is characterized by a symmetric proximal weakness starting from the legs, atrioventricular conduction disturbances and dysrhythmias. 17-year-old female patient had suffered from progressive muscle weakness. Patient's testing of deep-tendon reflexes were negative in neurological examination. She had positive Gower's sign and proximal muscle strength was reduced with score of 4/5. She had foot-drop gait and atrophy of lower extremities. Her feet showed a mild pescavus deformity and could not lift up by herself. Serum creatine kinase level was normal. Followed by pediatric cardiology due to first degree A–V block. Cardiac echocardiogram demonstration was normal. Nerve conduction velocity was within normal limits and electromyogram was indicative of myopathy. Muscular histology was compatible with muscular dystrophy and showed a nonspecific excess of lipid droplets. With the diagnosis of Limb Girdle muscular dystrophy 1B; LMNA gene sequence analysis including all coding exons and exon-intron boundaries was done and LMNA NM_170707.3:c.734T>C; (p.Leu245Pro) heterozygous missense mutation was detected. This mutation was first reported by from Turkish population. In silico analysis with Mutation Taster, Polyphen2, SIFT was predict this variant as a disease causing mutation. In order to show familial segregation, mother and father also were included in the study. Her parents were no carriers of the mutation. This case illustrate the necessity of correct diagnosis, evaluation, and follow up of cardiac problems due to the wide clinical spectrum and high prevalence of cardiac conduction block in patients with LGMD1B.

Early-Onset LMNA-Associated Muscular Dystrophy with Later Involvement of Contracture.

Background and PurposeThe early diagnosis of LMNA-associated muscular dystrophy is important for preventing sudden arrest related to cardiac conduction block. However, diagnosing early-onset Emery-Dreifuss muscular dystrophy (EDMD) with later involvement of contracture and limb-girdle muscular dystrophy type 1B is often delayed due to heterogeneous clinical presentations. We aimed to determine the clinical features that contribute to a delayed diagnosis.MethodsWe reviewed four patients who were recently diagnosed with LMNA-associated muscular dystrophy by targeted exome sequencing and who were initially diagnosed with nonspecific or other types of muscular dystrophy.ResultsCertain clinical features such as delayed contracture involvement and calf hypertrophy were found to contribute to a delayed diagnosis. Muscle biopsies were not informative for the diagnosis in these patients.ConclusionsGenetic testing of single or multiple genes is useful for confirming a diagnosis of LMNA-associated muscular dystrophy. Even EDMD patients could experience the later involvement of contracture, so clinicians should consider early genetic testing for patients with undiagnosed muscular dystrophy or laminopathy.