Cardiomyopathy related desmocollin-2 prodomain variants affect the intracellular cadherin transport and processing.

Background: Arrhythmogenic cardiomyopathy can be caused by genetic variants in desmosomal cadherins. Since cardiac desmosomal cadherins are crucial for cell-cell-adhesion, their correct localization at the plasma membrane is essential. Methods: Nine desmocollin-2 variants at five positions from various public genetic databases (p.D30N, p.V52A/I, p.G77V/D/S, p.V79G, p.I96V/T) and three additional conserved positions (p.C32, p.C57, p.F71) within the prodomain were investigated in vitro using confocal microscopy. Model variants (p.C32A/S, p.V52G/L, p.C57A/S, p.F71Y/A/S, p.V79A/I/L, p.I96l/A) were generated to investigate the impact of specific amino acids. Results: We revealed that all analyzed positions in the prodomain are critical for the intracellular transport. However, the variants p.D30N, p.V52A/I and p.I96V listed in genetic databases do not disturb the intracellular transport revealing that the loss of these canonical sequences may be compensated. Conclusion: As disease-related homozygous truncating desmocollin-2 variants lacking the transmembrane domain are not localized at the plasma membrane, we predict that some of the investigated prodomain variants may be relevant in the context of arrhythmogenic cardiomyopathy due to disturbed intracellular transport.

Evolution and triggers of defibrillator shocks in patients with arrhythmogenic right ventricular cardiomyopathy.

INTRODUCTION: Implantable cardioverter-defibrillators (ICDs) can prevent sudden cardiac death due to ventricular arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). The aim of our study was to assess the cumulative burden, evolution and potential triggers of appropriate ICD shocks during long-term follow-up, which may help to reduce and further refine individual arrhythmic risk in this challenging disease. METHODS: This retrospective cohort study included 53 patients with definite ARVC according to the 2010 Task Force Criteria from the multicentre Swiss ARVC Registry with an implanted ICD for primary or secondary prevention. Follow-up was conducted by assessing all available patient records from patient visits, hospitalisations, blood samples, genetic analysis, as well as device interrogation and tracings. RESULTS: Fifty-three patients (male 71.7%, mean age 43±2.2 years, genotype positive 58.5%) were analysed during a median follow-up of 7.9 (IQR 10) years. In 29 (54.7%) patients, 177 appropriate ICD shocks associated with 71 shock episodes occurred. Median time to first appropriate ICD shock was 2.8 (IQR 3.6) years. Long-term risk of shocks remained high throughout long-term follow-up. Shock episodes occurred mainly during daytime (91.5%, n=65) and without seasonal preference. We identified potentially reversible triggers in 56 of 71 (78.9%) appropriate shock episodes, the main triggers representing physical activity, inflammation and hypokalaemia. CONCLUSION: The long-term risk of appropriate ICD shocks in patients with ARVC remains high during long-term follow-up. Ventricular arrhythmias occur more often during daytime, without seasonal preference. Reversible triggers are frequent with the most common triggers for appropriate ICD shocks being physical activity, inflammation and hypokalaemia in this patient population.

Circulating Biomarkers of Fibrosis Formation in Patients with Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is a progressive inheritable disease which is characterized by a gradual fibro-(fatty) replacement of the myocardium. Visualization of diffuse and patchy fibrosis patterns is challenging using clinically applied cardiac imaging modalities (e.g., late gadolinium enhancement, LGE). During collagen synthesis and breakdown, carboxy-peptides are released into the bloodstream, specifically procollagen type-I carboxy-terminal propeptides (PICP) and collagen type-I carboxy-terminal telopeptides (ICTP). We collected the serum and EDTA blood samples and clinical data of 45 ACM patients (age 50.11 ± 15.53 years, 44% female), divided into 35 diagnosed ACM patients with a 2010 ARVC Task Force Criteria score (TFC) ≥ 4, and 10 preclinical variant carriers with a TFC < 4. PICP levels were measured using an enzyme-linked immune sorbent assay and ICTP levels with a radio immunoassay. Increased PICP/ICTP ratios suggest a higher collagen deposition. We found significantly higher PICP and PICP/ICTP levels in diagnosed patients compared to preclinical variant carriers (p < 0.036 and p < 0.027). A moderate negative correlation existed between right ventricular ejection fractions (RVEF) and the PICP/ICTP ratio (r = -0.46, p = 0.06). In addition, significant correlations with left ventricular function (LVEF r = -0.53, p = 0.03 and end-systolic volume r = 0.63, p = 0.02) were found. These findings indicate impaired contractile performance due to pro-fibrotic remodeling. Follow-up studies including a larger number of patients should be performed to substantiate our findings and the validity of those levels as potential promising biomarkers in ACM.

Frontal QRS - T angle is associated with severity and prognosis of acute pulmonary embolism.

INTRODUCTION: The pathological effects of acute pulmonary embolism (APE) on the right ventricle are one of the most important determinants of mortality in patients with APE. Frontal QRS-T angle (fQRSTa) predicts ventricular pathology and poor prognosis in many different cardiovascular diseases. In this study, we investigated whether there is a significant relationship between fQRSTa and APE severity. MATERIAL AND METHODS: A total of 309 patients were included in this retrospective study. The severity of APE was classified as massive (high risk), submassive (intermediate risk), or nonmassive (low risk). fQRSTa calculated from standard ECGs. RESULTS: fQRSTa was significantly higher in massive APE patients (p < 0.001). fQRSTa was also found to be significantly higher in the in-hospital mortality group (p < 0.001). fQRSTa was an independent risk factor for the development of massive APE (odds ratio:1.033; 95% CI: 1.012-1.052; p < 0.001). CONCLUSION: Our study showed that increased fQRSTa predicts high-risk APE patients and mortality in APE patients.

A Novel Heterozygous Desmoplakin Variant Causes Cardiocutaneous Syndrome with Arrhythmogenic Cardiomyopathy and Palmoplantar Keratosis.

Cardiocutaneous syndrome (CCS) is often caused by genetic variants in desmoplakin (DSP) in the presence of thick calluses on the hands and soles of the feet (palmoplantar keratoderma) in combination with arrhythmogenic cardiomyopathy. In this case report, we describe a 58-year-old man presenting with a history of cardiomyopathy with recurrent sustained ventricular tachycardia and palmoplantar keratosis. The cardiological evaluation showed biventricular cardiomyopathy, and repeated genetic testing identified a novel DSP variant. Repeated genetic testingis clinically meaningful in patients with a high probability of a specific inherited cardiac disease, such as CCS, particularly if molecular screening has been performed in the pre-NGS era with an incomplete NGS panel or outdated technology as presented in this case report.

Biventricular Arrhythmogenic Cardiomyopathy Associated with a Novel Heterozygous Plakophilin-2 Early Truncating Variant.

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a hereditary condition that can cause sudden cardiac death in young, frequently athletic individuals under the age of 35 due to malignant arrhythmias. Competitive and endurance exercise may hasten the onset and progression of ARVC, leading to right ventricular dysfunction and potentially fatal ventricular arrhythmias earlier in life. In this article, we present a novel, pathogenic, early truncating heterozygous variant in the PKP2 gene that causes biventricular arrhythmogenic cardiomyopathy and affects a family, of which the only member with the positive phenotype is a competitive endurance athlete.

Safety and Feasibility of Catheter Ablation Procedures in Patients with Bleeding Disorders.

Aims/Objectives: Patients with bleeding disorders are a rare and complex population in catheter ablation (CA) procedures. The most common types of bleeding disorders are von Willebrand disease (VWD) and hemophilia A (HA). Patients with VWD or HA tend to have a higher risk of bleeding complications compared to other patients. There is a lack of data concerning peri- and postinterventional coagulation treatment. We sought to assess the optimal management of patients with VWD and HA referred for catheter ablation procedures. Methods and Results: In this study, we analyzed patients with VWD or HA undergoing CA procedures at two centers in Germany and Switzerland between 2016 and 2021. Clotting factors were administered in conjunction with hemostaseological recommendations. CA was performed as per the institutional standard. During the procedure, unfractionated heparin (UFH) was given intravenously with respect to the activated clotting time (ACT). Primary endpoints included the feasibility of the procedure, bleeding complications, and thromboembolic events during the procedure. Secondary endpoints included bleeding complications and thromboembolic events up to one year after catheter ablation. A total of seven patients (three VWD Type I, one VWD Type IIa, three HA) underwent 10 catheter ablation procedures (pulmonary vein isolation (PVI): two × radiofrequency (RF), one × laser balloon (LB), one × cryoballoon (CB); PVI + cavotricuspid isthmus (CTI): one × RF; PVI + left atrial appendage isolation (LAAI): one × RF; Premature ventricular contraction (PVC): three × RF; Atrioventricular nodal reentrant tachycardia (AVNRT): one × RF). VWD patients received 2000−3000 IE Wilate i.v. 30 to 45 min prior to ablation. Patients with HA received 2000−3000 IE factor VIII before the procedure. All patients undergoing PVI received UFH (cumulative dose 9000−18,000 IE) with a target ACT of >300 s. All patients after PVI were started on oral anticoagulation (OAC) 12 h after ablation. Two patients received aspirin (acetylsalicylic acid; ASA) for 4 weeks after the ablation of left-sided PVCs. No anticoagulation was prescribed after slow pathway modulation in a case with AVNRT. No bleeding complications or thromboembolic events were reported. During a follow-up of one year, one case of gastrointestinal bleeding occurred following OAC withdrawal after LAA occlusion. Conclusions: After the substitution of clotting factors, catheter ablation in patients with VWD and HA seems to be safe and feasible.

What's New in Arrhythmogenic Cardiomyopathies.

Arrhythmogenic Cardiomyopathy (ACM) is a hereditary cardiomyopathy often presenting with sudden cardiac death (SCD) in young athletic individuals [...].

Tissue Doppler echocardiography and outcome in arrhythmogenic right ventricular cardiomyopathy.

AIMS: This study aimed at investigating whether tissue Doppler imaging (TDI) is associated with adverse events in arrhythmogenic right ventricular cardiomyopathy (ARVC). METHODS AND RESULTS: Transthoracic echocardiography was performed in 72 patients with definite (n = 63) or borderline (n = 9) ARVC diagnosed according to the 2010 Task Force Criteria and included in the prospective Zurich ARVC registry. Myocardial peak systolic tissue velocity (S') was measured by TDI at lateral tricuspid (tricuspid S'), medial mitral (septal S'), and lateral mitral annulus (lateral S'). Association of echocardiographic parameters with outcome was assessed by univariable Cox regression. During a median follow-up of 4.9 ± 2.6 years, 6 (8.3%) patients died of cardiovascular cause or received heart transplantation and 21 (29.2%) patients developed sustained ventricular arrhythmia. Tricuspid, septal, and lateral S' were lower in patients who died (p = 0.001; p < 0.001; p = 0.008; respectively), while tricuspid and septal S' were lower in those with ventricular arrhythmia (p = 0.001; p = 0.008; respectively). There was a significant association of tricuspid, septal, and lateral S' with mortality (HR = 1.61, p = 0.011; HR = 2.15, p = 0.007; HR = 1.67, p = 0.017; respectively), while tricuspid and septal S' were associated with ventricular arrhythmia (HR = 1.20, p = 0.022; HR = 1.37, p = 0.004; respectively). Kaplan-Meier analyses demonstrated a higher freedom from mortality with tricuspid S' >8 cm/s (p = 0.001) and from ventricular arrhythmia with S' >10.5 cm/s (p = 0.021). CONCLUSIONS: This study demonstrates that TDI provides information on the ARVC phenotype, is associated with adverse events in ARVC patients, and differentiates between patients with and without adverse events.

The transition of the tachycardia from narrow to wide by a spontaneous atrial premature beat: What is the mechanism?

The transition of the tachycardia from narrow to wide by a spontaneous atrial premature contraction causing a long-short sequence and right bundle branch block.

A dual nodal response to the parahisian pacing and induction of the retrograde right bundle branch block maneuvers.

We presented intracardiac electrograms during the parahisian pacing, which represent three types of retrograde conduction and focus on the mechanism of types of retrograde conduction on wide QRS complexes and conclude that the two types of QRS of the retrograde conduction resulted from the presence or absence of retrograde block at the right bundle branch.

Diabetic microvascular complications associated with myocardial repolarization heterogeneity evaluated by Tp-e interval and Tp-e/QTc ratio.

INTRODUCTION: The heterogeneity in myocardial repolarization increases the risk of ventricular arrhythmias and sudden death in patients with diabetes mellitus (DM). The Tp-e interval and Tp-e/QTc ratio are found to be useful in the prediction of ventricular arrhythmias. In this study, we aimed to investigate the Tp-e interval and Tp-e/QTc ratio in diabetic patients with and without microvascular complications. MATERIALS AND METHODS: This cross-sectional observational study included patients with type 2 DM who presented to the endocrinology outpatient clinic. Diabetic microvascular complications were evaluated. The Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio were also calculated. RESULTS: A total of 240 patients with type 2 DM (148 patients had microvascular complications) were included in the study. Diabetic neuropathy rate was 30.4%, diabetic nephropathy rate was 38.4%, and diabetic retinopathy rate was 21.7%. Upon comparing patients according to Tp-e/QTc ratio, the median Tp-e/QTc interval of the group of patients with complications was 0.21 (0.19-0.23) and the median Tp-e/QTc ratio of the group of patients without complications was 0.19 (0.18-0.20) (p < 0.001). When patients were grouped according to the presence and severity of retinopathy, the Tp-e/QTc ratio was more prolonged in the proliferative retinopathy group [0.27 (0.23-0.30)] than the non-proliferative retinopathy group [0.20 (0.19-0.22), p < 0.001]. When patients were grouped according to the presence and severity of nephropathy, the Tp-e/QTc ratio was more prolonged in the macroalbuminuria and microalbuminuria group than the normoalbuminuric group [0.25 (0.21-0.30), 0.23 (0.19-0.24), and 0.19 (0.20-0.22), respectively, p = 0.002]. CONCLUSIONS: Our study is the first to demonstrate the association of the Tp-e interval and Tp-e/QTc ratio with the presence and severity of microvascular complications in patients with type 2 DM.

Relationship between right ventricular dilatation and blood copeptin levels in patients with acute pulmonary embolism.

PURPOSE: In this study, we aimed to investigate the importance of copeptin in the diagnosis of acute pulmonary embolism, detection of right ventricular dilatation and clinical severity and prognosis of pulmonary embolism. MATERIALS AND METHODS: In the study three groups were created; Group 1: Pulmonary embolism patients with right ventricular dilatation in echocardiography, Group 2: Pulmonary embolism patients without right ventricular dilatation in echocardiography, Group 3: Healthy people. Five mL of venous blood was collected for the measurement of serum copeptin from the patients and control group. D-dimer and troponin were studied with routine blood samples. Complaints, symptom and physical examination findings, tomography and echocardiography results, laboratory results of patients and treatments they received were recorded for the statistical analysis. RESULTS: Copeptin levels of acute pulmonary embolism patients were significantly higher than healthy individuals (P < 0.001). Copeptin values of Group 1 patients were significantly higher than Group 2 patients and Group 3 patients (P < 0.001). There was a statistically significant difference the levels of copeptin, D-dimer and troponin between patients with right ventricular dilatation and patients without right ventricular dilatation (P < 0.05). AUC value in detecting right ventricular dilatation of copeptin was found to be 0.82, while specificity was 83.3% and sensitivity was 69.6%. Copeptin, D-dimer and troponin levels of patients with increased pulmonary artery pressure were statistically significantly higher than patients with normal pulmonary artery pressure (P < 0.05). CONCLUSION: Copeptin can be used in the diagnosis of acute pulmonary embolism and in the detection of right ventricular dilatation in pulmonary embolism.

Relationship between serum bilirubin levels and presence of fragmented QRS in patients with acute coronary syndrome.

Aim: To assess the relationship between serum bilirubin levels and fragmented QRS (fQRS), and their association with adverse events in patients with acute coronary syndrome. Methods: This study included a total of 736 patients. Laboratory results such as bilirubin levels, renal and liver function tests were obtained from the first available blood sample. Results: Left ventricular ejection fraction, end-diastolic diameter and total bilirubin level were significantly lower in fQRS (+) group than in the control group (45.0 [40.0-55.0] vs 50.0 [45.0-60.0]%; p < 0.001; 4.7 [4.6-5.1] vs 4.7 [4.5-4.9] cm; p < 0.001; 0.66 [0.49-5.1] vs 0.72 [0.53-0.97] md/dl; p = 0.017); respectively. Occurrence of adverse events was significantly higher in fQRS (+) group (32.5 vs 20.5 %; p = 0.013) during mean 1-year follow-up period. Conclusion: Total bilirubin level is an independent predictor of fQRS formation, which is associated with the presence of adverse events in patients with acute coronary syndrome.

Comparison of atrial fibrillation predictors in patients with acute coronary syndrome using ticagrelor or clopidogrel

Background/aim: Ticagrelor is a drug widely used in patients with acute coronary syndromes (ACS) that specifically increases the plasma level of adenosine, which is likely to cause atrial fibrillation (AF). Therefore, in this study we aimed to investigate the electrocardiographic and echocardiographic predictors of AF development after P2Y12 receptor antagonists in ACS patients. Materials and methods: This cross-sectional study included 831 patients with ACS (486 [58.5%] with ST elevated myocardial infarction [STEMI] and 345 [41.5%] with non-ST elevated myocardial infarction [NSTEMI]). Patients were divided into ticagrelor (n = 410) and clopidogrel (n = 421) groups. P wave properties including P wave dispersion and atrial electromechanical conduction properties were measured as AF predictors with surface ECG and tissue Doppler imaging. Results: Baseline characteristics such as age, sex, heart rate, blood pressure, and laboratory parameters were almost the same in the ticagrelor and clopidogrel groups. The statistical analysis showed no significant difference in P wave dispersion (PWD) between ticagrelor and clopidogrel groups (40.98 ± 12 ms versus 40.06 ± 12 ms, P = 0.304). Subgroups analysis according to ACS types also showed no significant difference in PWD (NSTEMI: 41.16 ± 13.8 ms versus 40.76 ± 13.55 ms, P = 0.799; STEMI: 40.9 ± 12.62 ms versus 39.19 ± 11.18 ms, P = 0.132). In addition, we did not find significant difference in atrial electromechanical delay (EMD) with tissue Doppler imaging (interatrial EMD 24.11 ± 3.06 ms versus 24.46 ± 3.23 ms, P = 0.279). Conclusion: In conclusion, we did not find any difference in detailed electrocardiographic and echocardiographic parameters as AF predictors between ticagrelor and clopidogrel groups in patients with ACS

Red blood cell distribution width as a predictor of long-term mortality in patients with carbon monoxide poisoning.

OBJECTIVES: Elevated red blood cell distribution width (RDW) is an independent prognostic factor for cardiovascular events that are major causes of mortality in patients with carbon monoxide (CO) poisoning. Due to the limited number of studies, we aimed to investigate the relationship between RDW levels and long-term mortality for these patients. METHOD: This retrospective study included patients with CO poisoning, who presented to the emergency department. Baseline characteristics, laboratory results and survival status were retrieved from patients' hospital records. The severity of poisoning was determined according to COHb level and/or clinical signs and symptoms. RESULTS: The study included 571 patients (median age was 37.0 years) and less than half of these patients were male (n = 206, 36.1%). There were mild-moderate CO poisoning in 389 (68.1%) patients and severe poisoning in 182 (31.9%). At a median follow-up of 6.2 years, there were 33 deaths (5.8%). Univariate cox-regression analysis demonstrated that age, gender, presence of hypertension or diabetes mellitus, levels of hemoglobin, RDW, creatinine and alanine-aminotransferase, and white-blood-cell count were potential covariates of long-term all-cause mortality. In the multivariate analysis, the median age and RDW level remained independent predictors of mortality (age, Odds ratio [OR]: 1.070 95% confidence interval [CI]: 1.030-1.110, p = 0.001; RDW, OR: 1.221 95% CI: 1.042-1.431, p = 0.013). Patients with higher RDW levels had a significantly worse prognosis in terms of mortality than with lower RDW levels (log-rank test, p = 0.003). CONCLUSION: This study demonstrated that RDW level is an independent predictor of long-term mortality in patients with CO poisoning.

Pulmonary Arterial Hemodynamic Assessment by a Novel Index in Systemic Sclerosis Patients: Pulmonary Pulse Transit Time.

OBJECTIVES: Systemic sclerosis (SSc) is a chronic, inflammatory, and autoimmune connective tissue disease that is associated with vascular lesions, and fibrosis of the skin and visceral organs. Cardiac complications may occur as a secondary effect of SSc as a result of pulmonary arterial hypertension and interstitial lung disease. The objective of this study was to assess whether the pulmonary pulse transit time (pPTT) could serve as a diagnostic marker for pulmonary arterial alterations in patients with SSc, prior to development of pulmonary hypertension. METHODS: Twenty-five SSc patients as a study group and 25 age- and sex-matched healthy volunteers for the control group were recruited to the study. Right ventricle function parameters, such as tricuspid annular plane systolic excursion (TAPSE), estimated pulmonary artery systolic pressure (ePASP), right ventricular dimensions, right ventricle fractional area changes, and myocardial perfusion index (MPI) were measured and calculated. Pulmonary pulse transit time was defined as the time interval between the R-wave peak in the ECG and the corresponding peak late systolic pulmonary vein flow velocity. RESULTS: Right ventricle myocardial performance index (RVMPI) and eSPAP were significantly higher in the SSc group than the controls (p = 0.032, p = 0.012, respectively). Pulmonary pulse transit time and TAPSE was shorter in the patients with SSc (p = 0.006, p = 0.015, respectively). In correlation analysis, pPTT was inversely correlated with RVMPI (r = - 0.435, p = 0.003), eSPAP (r = - 0.434, p = 0.003), and disease duration (r = - 0.595, p = 0.003). Conversely, it positively correlated with TAPSE (r = 0.345, p = 0.022). CONCLUSION: pPTT was found to be shorter in SSc patients. pPTT might serve as a surrogate marker of pulmonary hemodynamics in patients with SSc, even prior to the development of pulmonary hypertension.

Flash pulmonary edema: A rare cause and possible mechanisms.

Flash pulmonary edema frequently develop in case of bilateral renal artery stenosis and unilateral renal artery stenosis with functional solitary kidney. In some rare cases, unilateral renal artery stenosis with bilaterally functional kidneys may also lead to flash pulmonary edema. Here, we present a case of flash pulmonary edema caused by accessory renal artery stenosis. To our knowledge, it is the first case reported in the literature.

Pulmonary arterial hemodynamic assessment by a novel index in systemic lupus erythematosus patients: pulmonary pulse transit time.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic, inflammatory, and autoimmune connective tissue disease. One of the leading causes of mortality among SLE patients is pulmonary hypertension. The aim of this study was to evaluate the association between echocardiographic findings, including the pulmonary pulse transit time and pulmonary hypertension parameters, in SLE patients. METHODS: Thirty SLE patients (aged 39.9±11 years, 28 females) as the study group and 34 age- and sex-matched healthy volunteers (aged 37.9±11.5 years, 31 females) as the control group were included in the study. After detailed medical histories were recorded, 12-lead electrocardiography, blood tests, and echocardiography were performed in the groups. In addition to basic echocardiographic measurements, other specialized right ventricular indicators [i.e, Tricuspid Annular Plane Systolic Excursion (TAPSE), estimated pulmonary artery systolic pressure (ePASP), right ventricular dimensions, and myocardial performance index (MPI)] were measured. The pulmonary pulse transit time was defined as the time interval between the R-wave peak in ECG and the corresponding peak late-systolic pulmonary vein flow velocity. RESULTS: The mean disease duration was 121.1±49.9 months. The mean age at diagnosis was 35.0±15.4 years. The mean RV MPI was higher (p=0.026), mean TAPSE measurements were shorter (p=0.021), and mean ePASP was higher (p=0.036) in the SLE group than in the control group. In addition, pPTT was significantly shorter in the SLE group (p=0.003). pPTT was inversely correlated with disease duration (p<0.001), MPI (p=0.037), and ePASP (p=0.02) and positively correlated with TAPSE (p<0.001). CONCLUSION: SLE patients have higher pPTT values than controls. Further, pPTT shows an inverse correlation with disease duration, MPI, and ePASP and a positive correlation with TAPSE.