Factors and mechanisms that activate macrophages in atherosclerotic plaques are incompletely understood. We examined the capacity of heparanase to activate macrophages.
Highly purified heparanase was ...added to mouse peritoneal macrophages and macrophage-like J774 cells, and the levels of tumor necrosis factor-α, matrix metalloproteinase-9, interlukin-1, and monocyte chemotactic protein-1 were evaluated by ELISA. Gene expression was determined by RT-PCR. Cells collected from Toll-like receptor-2 and Toll-like receptor-4 knockout mice were evaluated similarly. Heparanase levels in the plasma of patients with acute myocardial infarction, stable angina, and healthy subjects were determined by ELISA. Immunohistochemistry was applied to detect the expression of heparanase in control specimens and specimens of patients with stable angina or acute myocardial infarction. Addition or overexpression of heparanase variants resulted in marked increase in tumor necrosis factor-α, matrix metalloproteinase-9, interlukin-1, and monocyte chemotactic protein-1 levels. Mouse peritoneal macrophages harvested from Toll-like receptor-2 or Toll-like receptor-4 knockout mice were not activated by heparanase. Plasma heparanase level was higher in patients with acute myocardial infarction, compared with patients with stable angina and healthy subjects. Pathologic coronary specimens obtained from vulnerable plaques showed increased heparanase staining compared with specimens of stable plaque and controls.
Heparanase activates macrophages, resulting in marked induction of cytokine expression associated with plaque progression toward vulnerability.
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.
Heparanase, the sole mammalian endoglycosidase degrading heparan sulfate, is causally involved in cancer metastasis, angiogenesis, inflammation and kidney dysfunction. Despite the wide occurrence and ...impact of heparan sulfate proteoglycans in vascular biology, the significance of heparanase in vessel wall disorders is underestimated. Blood vessels are highly active structures whose morphology rapidly adapts to maintain vascular function under altered systemic and local conditions. In some pathologies (restenosis, thrombosis, atherosclerosis) this normally beneficial adaptation may be detrimental to overall function. Enzymatic dependent and independent effects of heparanase on arterial structure mechanics and repair closely regulate arterial compliance and neointimal proliferation following endovascular stenting. Additionally, heparanase promotes thrombosis after vascular injury and contributes to a pro-coagulant state in human carotid atherosclerosis. Importantly, heparanase is closely associated with development and progression of atherosclerotic plaques, including stable to unstable plaque transition. Consequently, heparanase levels are markedly increased in the plasma of patients with acute myocardial infarction. Noteworthy, heparanase activates macrophages, resulting in marked induction of cytokine expression associated with plaque progression towards vulnerability. Together, heparanase emerges as a regulator of vulnerable lesion development and potential target for therapeutic intervention in atherosclerosis and related vessel wall complications.
Dilated cardiomyopathy (DCM) caused by Lamin A/C gene (LMNA) mutation is complicated with atrioventricular conduction disturbances, malignant ventricular arrhythmias and progressive severe heart ...failure.
We hypothesized that early cardiac resynchronization therapy (CRT) implantation in LMNA mutation carriers with an established indication for pacemaker or implantable cardioverter defibrillator (ICD), may preserve ejection fraction, and delay disease progression to end stage heart failure.
We compared the primary outcomes: time to heart transplantation, death due to end stage heart failure or ventricular tachycardia (VT) ablation and secondary outcomes: change in left ventricular ejection fraction (EF) and ventricular arrhythmia burden between LMNA DCM patients in the early CRT and non-CRT groups.
Of ten LMNA DCM patients (age 51±10 years, QRS 96±14 msec, EF 55±7%) with indication for pacemaker or ICD implantation, five underwent early CRT-D implantation. After 7.2±4 years, three patients (60%) in the non-CRT group reached the primary outcome, compared to no patients in the CRT group (P=0.046). Four patients in non-CRT group (80%) experienced sustained ventricular tachycardia or received appropriate ICD shock compared to 1 patient (20%) in the CRT group (P=0.058). LMNA patients without early CRT had a higher burden of VPC/24 h in 12-lead holter (median 2352 vs 185, P=0.09). Echocardiography showed statistically lower LVEF in the non-CRT group compared to CRT group (32±15)% vs (61±4)%, 95% CI: 32.97-61.03, P=0.016.
Early CRT implantation in LMNA cardiomyopathy patients, with an indication for pacemaker or ICD, may reduce heart failure deterioration and life-threatening heart failure complications.
Arrhythmogenic cardiomyopathy (AC) is an inherited cardiomyopathy characterized by fibro-fatty replacement of cardiomyocytes, leading to life-threatening ventricular arrhythmia and heart failure. ...Pathogenic variants of desmoglein2 gene (DSG2) have been reported as genetic etiologies of AC. In contrast, many reported DSG2 variants are benign or variants of uncertain significance. Correct genetic variant classification is crucial for determining the best medical therapy for the patient and family members.
Pathogenicity of the DSG2 Ser194Leu variant that was identified by whole exome sequencing in a patient, who presented with ventricular tachycardia and was diagnosed with AC, was investigated by electron microscopy and immunohistochemical staining of endomyocardial biopsy sample.
Electron microscopy demonstrated a widened gap in the adhering junction and a less well-organized intercalated disk region in the mutated cardiomyocytes compared to the control. Immunohistochemical staining in the proband diagnosed with AC showed reduced expression of desmoglein 2 and connexin 43 and intercalated disc distortion. Reduced expression of DSG2 and Connexin 43 were observed in cellular cytoplasm and gap junctions. Additionally, we detected perinuclear accumulation of DSG2 and Connexin 43 in the proband sample.
Ser194Leu is a missense pathogenic mutation of DSG2 gene associated with arrhythmogenic left ventricular cardiomyopathy.
Background
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare but highly malignant inherited arrhythmic disorder. Although a standardized exercise stress test (ST) is the most ...reliable way to diagnose CPVT, in 30% only single ventricular premature beats (VPCs) were recorded.
Objective
To evaluate whether electrocardiographic characteristics of VPCs during ST distinguish patients with CPVT from healthy subjects.
Methods
Electrocardiographic characteristics of VPCs during ST in 16 calsequestrin‐2 (CASQ2) mutation carriers CPVT patients were compared with that in 36 healthy subjects.
Results
CPVT patients had more VPCs (31 ± 14 vs 3 ± 4, P < 0.0001), longer QRS duration (139 ± 18 ms vs 121 ± 21, P = 0.004), and coupling interval (CI; 476 ± 58 ms vs 355 ± 61 ms, P < 0.0001). The most sensitive characteristics for CPVT were >10 VPCs/test (100% sensitivity, 100% negative predictive value NPV), left bundle branch block (LBBB) pattern with inferior axis (88% sensitivity, 94% NPV), and CI longer than 400 ms (88% sensitivity, 94% NPV). Bigeminy or trigeminy or LBBB pattern with inferior axis was most specific for CPVT at 100% (100% positive predictive value PPV, 92% NPV). First VPC during the recovery period and VPC recording more than 1 minute during the recovery period were most specific for healthy subjects (100% specificity, 100% PPV). In multivariate analysis, QRS duration >120 ms (odds ratio 4.2, 95% confidence interval 1–17.6, P = 0.04) and first VPC at ≥10 mets (odds ratio 9.1, 95% confidence interval 2.01–41.1, P = 0.004) each predicted the presence of CPVT.
Conclusions
Several electrocardiographic criteria can help distinguish VPCs originating from CPVT compared with healthy subjects.
Congenital long QT syndrome (LQTS) is a cardiac channelopathy that leads to the prolongation of the QT interval. This prolongation can lead to ventricular tachyarrhythmia, syncope, and sudden cardiac ...death. There are various types of LQTS. Treatment of LQT1 and LQT2 is mainly based on antiadrenergic therapy. LQT3, on the other hand, is a result of a mutation of the SCN5A gene, which encodes the sodium channels. In this type, patients are sensitive to vagal stimuli and episodes tend to occur at rest. Sodium channel blocking compounds, such as ranolazine, mexiletine, and flecainide, have been found to be effective in selective mutations.In this case report, we report the case of a child with congenital LQT3 (V411M) who presented first with sudden cardiac death and three weeks later with an implantable cardioverter defibrillator storm. Knowing the specific mutation and understanding the mechanism at the molecular level through an in vitro study yielded a clinically meaningful result. The patient's arrhythmia burden was totally eliminated following successful treatment with flecainide.
Aims
To study the prevalence and long-term prognostic significance of changes in haemoglobin levels during hospital course in survivors of acute myocardial infarction (AMI).
Methods and results
A ...prospective study involving 1390 patients who were admitted with AMI. Median follow-up was 24 months. Multivariable Cox models were used to evaluate the relationship between nadir and discharge haemoglobin and mortality after hospital discharge. Anaemia was present in 248 patients on admission (17.8%) and in 502 patients at discharge (36.1%). Nadir haemoglobin during hospital course was 1.3 g/dL lower (IQR 0.6-2.2) when compared with baseline haemoglobin (P < 0.0001). Low nadir haemoglobin and discharge haemoglobin were strongly associated with increased mortality. After adjusting for clinical variables and ejection fraction, the hazard ratios for a 1 g/dL decrease in nadir haemoglobin and discharge haemoglobin were 1.36 (95% CI 1.19-1.55; P < 0.0001) and 1.27 (95% CI 1.16−1.40; P < 0.0001), respectively.
Conclusion
The development of anaemia during hospitalization for AMI is frequent and is associated with an increased long-term mortality.
Background
Ablation of outflow flow ventricular arrhythmia (VA) originating from aortic cusps can be challenging. The aim of this study was to describe our approach for this ablation.
Methods
All ...patients with outflow VA suspected to originate from aortic cusps according to ECG or after failed ablation from right ventricular outflow tract (RVOT) underwent cardiac CT and radiofrequency ablation. CT image of aortic cusps and coronary arteries was integrated into electroanatomic mapping system by point (left main ostium)-based registration. Ablation was performed at the earliest activation site.
Results
Ten patients were included in this case cohort. The ablation catheter was easily maneuvered above and below the aortic valve after registration. Two patients who had previous failed ablation of RVOT focus had successful ablation at right coronary cusp (RCC) and at left coronary cusp (LCC). A patient who had previous failed ablations of RVOT and LCC focuses had successful ablation at RCC-LCC junction. A patient who had previous failed ablation at LCC had successful ablation at RCC-LCC junction. Three patients had successful ablation at RCC-LCC junction, and one patient at LCC. One patient had successful ablation at anterior interventricular vein–great cardiac vein junction. One patient had successful ablation at non-coronary cusp. During follow-up (12–30 months), one patient had recurrence of VA controlled by flecainide. The remaining patients were free of VA without medications.
Conclusions
Catheter ablation of VA originating from aortic cusps is safe and effective. CT image integration into electroanatomic mapping system can be helpful in this challenging ablation.
To assess the effectiveness and to identify predictors for successful electrical cardioversion (ECV) and maintenance of sinus rhythm, in long term follow up of patients with persistent (PAF) and ...chronic atrial fibrillation (CAF).
Retrospective analysis of medical records of 68 patients with PAF or CAF, who underwent 91cardioversions. ECV was successful in 86 attempts (94.5%). In obese (body mass index
>
30) and hypertensive patients (blood pressure >
140/90 mm Hg), ECV was less successful in restoring sinus rhythm (
p
<
0.05,
p
<
0.021, respectively). Sinus rhythm was maintained more than half a year in 42 cardioversions (61%). Treatment with beta blockers prior to cardioversion and age younger than 75 were independent factors predicting long term success (
p
<
0.013,
p
<
0.034, respectively). Mild or moderate enlargement of left atrium (<
6 cm) did not predict relapse of the arrhythmia. Second ECV was as or more effective than the first in 82.3% of patients that underwent more than one cardioversion.
Conversion of atrial fibrillation by DC shock was found to be safe and effective procedure. Patients should be treated with beta blockers prior to cardioversion, if possible. Mild or moderate enlargement of left atrium is not contraindication to cardioversion. Recurrent cardioversions may be recommended.
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