Clinical Characteristics And Pathogenic Mechanism Of Right Ventricular Apical Pacing After Heart Failure And Left Ventricular Densification Of Cardiomyopathy

BackgroundThird degree atrioventricular block(AVB)is a common type of bradycardias that few effective drugs can cure.Right ventricular apical pacing(RVAP)is effective to treat III AVB.During recent decades,emerging studies have suggested RVAP can cause electrical and mechanical dyssynchrony and eventually induce adverse effects on myocardial metabolism and perfusion,remodeling,hemodynamics and mechanical function,finally lead to heart failure(HF).Usually,RVA pacing induced HF usually happens in patients with baseline cardiac dysfunction and high pacingburden;however,it can also occur in patients with normal baseline cardiac function.As the pathogenesis of HF involves a complex interaction between genetic and environmental factors.Genetic factors may influence the susceptibility to the underlying etiology of HF,the rapidity of disease progression,or the response to pharmacologic therapy.What's more,HF may also arise in the setting of a primary cardiomyopathy,most commonly dilated cardiomyopathy(DCM).ObjectsThis study aims to investigate the genetic mechanisms of the new-onset HF after RVA pacing in third degree atrioventricular block(III AVB)patients,and using transfected NRCMs to explore the pathogenic mechanism of RVA pacing induced cardiomyopathy.MethodsBetween January 1987 and December 2013,877 consecutive patients(mean age 57.4±18.4years,465 males)with III AVB were referred for cardiac pacemaker implantation in Fuwai Hospital(Beijing,China).Clinical follow-up discovered 10 cases diagnosed with RVA pacing induced HF.Candidate genetic screening was implemented in the HF patients and control patients,PCR,Western blot and fluorescence immunocytochemistry were used to detect the expression level of genes and proteins expression;Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling(TUNEL)was used to evaluate the apoptotic rate after serum starvation;Label-free proteomics analyze the dysregulated proteins between LaminA/C WT cells and muations cells.ResultsWe followed 887 III AVB patients with baseline normal cardiac function and RVA pacing.After a median follow-up of 2.5 years,31 patients(3.51%)were rehospitalized for severe symptoms of HF.Among them,10 patients(four males,mean age 47.6±10.0 years)were diagnosed with RVA pacing induced HF with left ventricular ejection fraction(LVEF)reducing dramatically from 60.5±5.9%to 37.8±7.1%(P<0.05).Candidate genes sequencing found all ten HF patients carried cardiomyopathy associated genetic variants including three different variants in Lamin A/C gene,14 of the control patients failed to find any genetic mutations,and six of them carried variants in SCN5A gene.Neonatal rat cardiomyocytes(NRCMs)transfected by Lamin A/C mutations(R216 and L379F)lentiviruses showed disrupted Lamin A/C location in nucleus membrane,Neonatal rat cardiomyocytes(NRCMs)were isolated and transfected with Lamin A/C WT and mutations(R216C and L379F)lentivirus,PCR and Western blot showed similar expression level of Lamin A/C in WT and mutations;fluorescence immunocytochemistry and Western blot demonstrated there were no significant differences in the expression level or location status of Nav1.5 and Cx43 proteins;TUNEL revealed significant increase in the apoptotic rate of Lamin A/C mutations cells after serum starvation;PANTHER analysis showed that 144 dysregulated proteins could be categorizd into 20 protein classes in which nucleic acid binding proteins consisted the largest group(21%).Molecular Function analysis revealed these proteins were most associated with binding(35%),and catalytic activity(31%).dysregulated proteins were mostly involved in cellular process(28%)and metabolic process(19%)and cellular component organization or biogenesis(10%)process.Reactome and STRING revealed that dysregulated proteins were mainly participate in the apoptosis pathways of PI3K-Akt signaling pathway and Ras signaling pathway(Figure 5F).ConclusionsCardiomyopathy associated genetic variations play an essential role on occurrence of newly onset HF in the III AVB patients with RVA pacing.RVA pacing,works as extra stimulator,might accelerate the deterioration of cardiac structure and function.and Lamin A/C mutations(R216C and L379F)can induce the apoptosis by disrupting the location of Lamin A/C proteins and nucleic acid binding that improve RVA induced cardiomyopathy development.Genetic testing may act as an effective strategy to identify patients with high risk of HF and explain the pathogenic mechanism.BackgroundLeft ventricular noncompaction cardiomyopathy(LVNC)is the third most common cardiomyopathy after dilated and hypertrophic cardiomyopathies,and its prevalence ranges between 0.05 and 0.3%,a genetic cardiomyopathy LVNC is characterized by prominent ventricular trabeculations and deep intertrabecular recess,or sinusoids,in communication with the left ventricular cavity.The clinical sequelae of these deformities are the syndrome of heart failure(HF)and the risk for arrhythmias including sudden cardiac death(SCD)and thrombi.LVNC is a class of heterogenetic disease lacking specific phenotype-genotype association.It has been previously shown that LVNC is associated with defects in TAZ,DNTA,LDB3,YWHAE,MIB1,PRDM16,and sarcomeric genes.It is generally believed that these gene mutations may share a final common pathway in the pathogenesis of LVNC,but the underlying molecular mechanisms are unknown.ObjectsTo investigate the clinical characteristics,long-term prognosis and genetic variants in Chinese LVNC cohort.MethodFrom March 2006 to March 2016,222 unrelated Chinese patients with LVNC were recruited at Fuwai Hospital,Beijing,China.The diagnosis of ILVNC was based on echocardiographic criteria proposed by Jenni et al.:(1)the presence of excessively prominent trabeculations and deep intertrabecular recesses;(2)intertrabecular recesses filled with intraventricular blood on color Doppler;(3)a maximal end-systolic ratio of the noncompacted endocardial layer to the compacted myocardium>2;(4)absence of other cardiac abnormalities.In the meantime,another proposed standardized method of identifying LVNC by CMRI was based on:(1)appearance of 2 distinct myocardial layers;(2)prominent myocardial trabeculations and deep intertrabecular recesses communicating with the LV cavity;(3)end-diastolic ratio of non-compacted-to-compacted(NC:C)myocardium>2.3:1,and(4)absence of other known co-existing cardiac abnormalities.Cases with discrepant diagnosis of LVNC were excluded from this study.Detailed clinical evaluation was performed on the probands and available family members.The medical history,electrocardiograms,cardiac MRI and echocardiograms of these patients were retrospectively analyzed by chart review.DNA samples isolated from the peripheral blood of the index cases were screened for 20 LVNA associated genes,including DTNA,CASQ2,LDB3,GATA4,ACTA1,HCN4,MYH7,LMNA,TNNT2,MYH7B,MIB1,NEXN,PRDM16,NNT,TPM1,RYR2,MYBPC3,YWHAE,TA2,ACTN2.ResultsA total of 222(149 male,mean age 43±14 years)sporadic patients were recruited,147 cases had HF and are significantly older than those without HF;Ventricular tachycardia(VT)and thrombi were found in 41 and 16 cases respectively.During a mean follow-up of 34 months,32 died with SCD in 14 individuals,16 patients underwent heart transplantation.Multiple regression analysis demonstrated the major risk factors for mortality were NYHA classIII/IV((hazard ratio(HR)3.502;95%confidence interval(CI)1.593-7.694;p<0.001)and LVEF(HR 0.925;95%CI 0.895-0.957;p<0.001).Besides,age(HR 1.073;95%CI 1.018-1.130;p=0.009)and LVEF(HR 0.881;95%CI 0.809-0.958;p=0.003)were the independent predictors of SCD.Serial echocardiography showed improved changes in LVEF in the HF survivors(%,33.7±8.0 vs.37.2±12.2,p<0.001)and the whole population(41.2112.8 vs.44.5±44.5±13.3,p=0.020).Genetic screening revealed 26/32 probands(24 male,mean age 3 5±17 years)being mutation positive.Five probands carried compound and/or double heterozygous variants.Variants found frequently were in MYH7B(18.8%),RYR2(15.3%),PRDM16(12.5%)and MYBPC3(12.5%).However,no significant difference was observed between mutation-positive and mutation-negative patients in clinical characteristics and mortality.ConclusionsThis study showed that LVNC is a genetically heterogeneous disease with progressive clinical course and high risk of death or heart transplantation.As the disease progress,the deterioration of cardiac structure and function would take place,coming along with ventricular arrhythmias,HF and other complications.Patients with severe HF symptoms and lower LVEF at baseline are prone to suffer poor outcomes and those with senile age are at high risk of SCD.On the other hand,when given optimal treatment or preventive management,HF patients may embrace better outcome.More genetic and functional studies should be conducted to reveal the etiology and pathogenesis of LVNC.