Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary heart muscle disorder resulting from desmosomal protein mutations. ARVC is characterized pathologically by fibrofatty infiltration ...and clinically by arrhythmias and sudden cardiac death. We aimed to establish a patient-/disease-specific human induced pluripotent stem cell (hiPSC) model of ARVC.
Dermal fibroblasts were obtained from 2 patients with ARVC with plakophilin-2 (PKP2) mutations, reprogrammed to generate hiPSCs, coaxed to differentiate into cardiomyocytes (CMs), and then compared with healthy control hiPSC-derived CMs (hiPSC-CMs). Real-time polymerase chain reaction showed a significant decrease in the expression of PKP2 in the ARVC-hiPSC-CMs. Immunostainings revealed reduced densities of PKP2, the associated desmosomal protein plakoglobin, and the gap-junction protein connexin-43. Electrophysiological assessment demonstrated prolonged field potential rise time in the ARVC-hiPSC-CMs. Transmission electron microscopy identified widened and distorted desmosomes in the ARVC-hiPSC-CMs. Clusters of lipid droplets were identified in the ARVC-CMs that displayed the more severe desmosomal pathology. This finding was associated with upregulation of the proadipogenic transcription factor peroxisome proliferator-activated receptor-γ. Exposure of the cells to apidogenic stimuli augmented desmosomal distortion and lipid accumulation. The latter phenomenon was prevented by application of a specific inhibitor of glycogen synthase kinase 3β (6-bromoindirubin-3'-oxime).
This study highlights the unique potential of the hiPSC technology for modeling inherited cardiac disorders in general and ARVC specifically. The hiPSC-CMs were demonstrated to recapitulate the ARVC phenotype in the dish, provide mechanistic insights into early disease pathogenesis, and provide a unique platform for drug discovery and testing in this disorder.
Abstract We report a case of a 55-year-old woman with idiopathic ventricular fibrillation (VF) who suffered from recurrent implantable cardioverter-defibrillator shocks triggered by short coupled ...ventricular premature beat (VPB). This VPB was mapped and ablated from the myocardium of right ventricle close to the lateral tricuspid annulus. < Learning objective: Triggering ventricular premature beat (VPB) in idiopathic ventricular fibrillation was reported to originate from the myocardium of right ventricular outflow tract or from Purkinje system. In this case, the origin of triggering VPB is the myocardium of right ventricle close to the lateral tricuspid annulus.>
Percutaneous closure of an atrial septal defect (ASD) has been established as a safe and effective alternative to surgical management. We describe a case of a 41-year-old patient in whom an Amplatzer ...septal occluder device was used to close a moderately large ASD and who subsequently developed incessant intra-atrial macro-reenterant tachycardia. The tachycardia was terminated by radiofrequency ablation guided by electroanatomical mapping.
Objective and Background
To evaluate the diagnostic and prognostic yield of a comprehensive protocol involving clinical and broad genetic testing in consecutive sudden cardiac arrest (SCA) ...population.
Determining the pathogenesis of non‐ischemic SCA is crucial for management and SCA prevention in other family members
Methods
Families with unexplained non‐ischemic SCA event underwent rigorous clinical and genetic protocol after referral to our inherited arrhythmia clinic, during 2011–2017.
Results
One hundred and four index cases, 29 ± 16 years, and 421 family members were studied. After a thorough evaluation, diagnosis was made in 80 (77%) of families. The most prevalent 47/104 (45%) diagnosis was inherited channelopathy. The genetic test was positive, in 37 /69 (54%) of patients. Using the Mann Whitney test, we found that electrocardiography (ECG) (effect size 0.5, p < .001), 12 lead Holter (effect size 0.33, p = .001) and family screening (effect size 0.4, p = .001) had the highest yield in reaching the final diagnosis. Family screening, genetic testing, and cardiac MRI were the exclusive modalities for final diagnosis in 14%, 9%, and 2% of families, respectively. Among 421 family members evaluated through cascade screening, 127 (30%), were diagnosed and medically treated. Nine family members from 25 (40%) patients who underwent implantable cardioverter defibrillator (ICD) implantation have experienced appropriate ICD shock.
Conclusions
A rigorous, systematic protocol in a specialized inherited arrhythmia clinic has a high diagnostic and prognostic yield. ECG, 12 lead Holter and family screening significantly increased the diagnostic yield. In nine families, without genetic testing, the diagnosis would have been missed.
Left cardiac sympathetic denervation (LCSD) was reported to be effective in patients with intractable ryanodine receptor mutation-associated catecholaminergic polymorphic ventricular tachycardia ...(CPVT).
To report our experience with LCSD in calsequestrin (CASQ2) mutation-associated CPVT.
LCSD was performed in three patients with CASQ2 mutation-associated CPVT with symptoms and exercise-induced ventricular arrhythmia despite high dose beta-blocker
None of them experienced symptoms or exercise-induced ventricular arrhythmia after LCSD. However, all had recurrence of symptoms and/or exercise-induced ventricular arrhythmia after 6 months (6-18 months).
LCSD conferred short-term suppression but less than optimal long-term suppression of exercise-induced ventricular arrhythmia among CASQ2-associated CPVT patients.
We aimed to study the relationship between C-reactive-protein (CRP), obtained within 12 to 24 h of symptoms onset, and long-term risk of death and heart failure (HF) in survivors of acute myocardial ...infarction (MI).
A robust inflammatory response is an integral component of the response to tissue injury during MI. The magnitude of the early inflammatory response to ischemic injury might be an important determinant of long-term outcome.
We prospectively studied 1,044 patients admitted with acute MI and discharged from hospital in stable condition.
During a median follow-up of 23 months (range, 6 to 42 months), 113 patients died and 112 developed HF. In a multivariable Cox regression model adjusting for clinical variables and predischarge ejection fraction, compared with patients in the first CRP quartile, the adjusted hazard ratios (HRs) for death progressively increased with higher quartiles of CRP (second quartile 1.4 95% confidence interval (CI) 0.6 to 2.9; third quartile 2.3 95% CI 1.2 to 4.6; fourth quartile 3.0 95% CI 1.5 to 5.7; for trend, p = 0.0002). Compared with patients in the first CRP quartile, the adjusted HRs for HF were: second quartile, 1.1 (95% CI 0.5 to 2.3); third quartile, 1.9 (95% CI 1.0 to 3.6); and fourth quartile, 2.1 (95% CI 1.2 to 3.9) (for trend, p = 0.005).
C-reactive-protein is a marker of long-term development of HF and mortality in patients with acute MI and provides prognostic information beyond that provided by conventional risk factors and the degree of left ventricular systolic dysfunction.
Stress hyperglycemia in patients with acute myocardial infarction has been associated with increased mortality. Most studies looked at the relationship between admission glucose (AG) and outcome; ...limited information is available about the clinical significance of fasting glucose (FG).
We prospectively studied the relationship between FG and 30-day mortality in 735 nondiabetic patients with acute myocardial infarction. FG (> or =8-hour fast within 24 hours of admission) and AG were measured in each patient. At 30 days, 9 deaths (2%) occurred in patients with normal FG, and 11 (10%), 14 (13%), and 31 (29%) deaths occurred in the first, second, and third tertiles of elevated FG, respectively. Compared with normal FG (<110 mg/dL), the adjusted OR for 30-day mortality progressively increased with higher tertiles of elevated FG (first tertile, 4.6; 95% CI, 1.7 to 12.7; P=0.003; second tertile, 6.4; 95% CI, 2.5 to 16.6; P<0.0001; third tertile, 11.5; 95% CI, 4.7 to 20.0; P<0.0001). Compared with patients categorized as having normal AG (<140 mg/d), the adjusted ORs for tertiles of elevated AG were as follows: first tertile, 1.4 (95% CI, 0.5 to 3.8; P=0.54); second tertile, 3.0 (95% CI, 1.3 to 7.0; P=0.01); and third tertile, 4.4 (95% CI, 2.0 to 9.7; P<0.0001). Compared with patients with normal FG and AG, the adjusted ORs for 30-day mortality were 0.71 (95% CI, 0.15 to 3.4; P=0.67) in patients with elevated AG and normal FG, 3.4 (95% CI, 1.1 to 10.4; P=0.03) for patients with normal AG glucose and elevated FG, and 9.6 (95% CI, 3.5 to 26.0; P<0.0001) for patients with both elevated FG and AG. Comparing nested models showed that including AG failed to improve the prediction of the model based on FG (chi2=5.4, 3 df, P=0.15). In contrast, the addition of FG classes to the model based on AG improved model prediction (chi2=22.4, 3 df, P<0.0001).
There is a graded relation between elevated FG and AG and 30-day mortality in patients with acute myocardial infarction. FG is superior to AG in the assessment of short-term risk.
Atrial Fibrillation (AF) is the most common sustained tachi-arrhythmia. Thrombus formation in the left atrial appendage (LAA) increases the risk of stroke and systemic embolism in patients with AF.
...The aim of this study was to compare thrombin generation in the LAA to the LA among patients with AF.
A cross-sectional study of consecutive patients with AF undergoing pulmonary veins catheter ablation. Blood samples from the femoral vein (FV), right atrium (RA), left atrium (LA), and LAA were collected during the catheter ablation procedures. Thrombin generation was assessed by a Calibrated Automated Thrombogram. The LAA-calibrated automated thrombogram parameters were compared with the RA, LA, and FV.
A total of 47 consecutive patients were enrolled in the study. The endogenous thrombin potential and peak height were significantly higher in the LAA compared with the LA, the mean differences and 95% CI between the LA and LAA were -378.9 (-680.5, -77.2) (nM∗min) and -66.7 (-119.6, -13.8) (nM) in the endogenous thrombin potential and peak height respectively.
In patients with AF undergoing catheter ablation, the LAA demonstrated increased thrombin generation compared with the LA. This finding might contribute to the understanding of why the LAA is more predisposed to thrombus formation than the LA.
NCT03795883
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•Thrombin generation may be a pivotal factor in thrombosis in atrial fibrillation (AF).•Blood samples were collected from the heart chambers during AF catheter ablation.•The left atrial appendage (LAA) exhibited increased thrombotic potential compared with the left atrium (LA).•The current study contributes to the understanding of the LAA predisposition to thrombosis.
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