Cardiac-Specific Deletion of Scn8a Mitigates Dravet Syndrome-Associated Sudden Death in Adults.

BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) is a fatal complication experienced by otherwise healthy epilepsy patients. Dravet syndrome (DS) is an inherited epileptic disorder resulting from loss of function of the voltage-gated sodium channel, NaV 1.1, and is associated with particularly high SUDEP risk. Evidence is mounting that NaVs abundant in the brain also occur in the heart, suggesting that the very molecular mechanisms underlying epilepsy could also precipitate cardiac arrhythmias and sudden death. Despite marked reduction of NaV 1.1 functional expression in DS, pathogenic late sodium current (INa,L) is paradoxically increased in DS hearts. However, the mechanisms by which DS directly impacts the heart to promote sudden death remain unclear. OBJECTIVES: In this study, the authors sought to provide evidence implicating remodeling of Na+ - and Ca2+ -handling machinery, including NaV 1.6 and Na+/Ca2+exchanger (NCX) within transverse (T)-tubules in DS-associated arrhythmias. METHODS: The authors undertook scanning ion conductance microscopy (SICM)-guided patch clamp, super-resolution microscopy, confocal Ca2+ imaging, and in vivo electrocardiography studies in Scn1a haploinsufficient murine model of DS. RESULTS: DS promotes INa,L in T-tubular nanodomains, but not in other subcellular regions. Consistent with increased NaV activity in these regions, super-resolution microscopy revealed increased NaV 1.6 density near Ca2+release channels, the ryanodine receptors (RyR2) and NCX in DS relative to WT hearts. The resulting INa,L in these regions promoted aberrant Ca2+ release, leading to ventricular arrhythmias in vivo. Cardiac-specific deletion of NaV 1.6 protects adult DS mice from increased T-tubular late NaV activity and the resulting arrhythmias, as well as sudden death. CONCLUSIONS: These data demonstrate that NaV 1.6 undergoes remodeling within T-tubules of adult DS hearts serving as a substrate for Ca2+ -mediated cardiac arrhythmias and may be a druggable target for the prevention of SUDEP in adult DS subjects.

NaV1.6 dysregulation within myocardial T-tubules by D96V calmodulin enhances proarrhythmic sodium and calcium mishandling.

Calmodulin (CaM) plays critical roles in cardiomyocytes, regulating Na+ (NaV) and L-type Ca2+ channels (LTCCs). LTCC dysregulation by mutant CaMs has been implicated in action potential duration (APD) prolongation and arrhythmogenic long QT (LQT) syndrome. Intriguingly, D96V-CaM prolongs APD more than other LQT-associated CaMs despite inducing comparable levels of LTCC dysfunction, suggesting dysregulation of other depolarizing channels. Here, we provide evidence implicating NaV dysregulation within transverse (T) tubules in D96V-CaM-associated arrhythmias. D96V-CaM induced a proarrhythmic late Na+ current (INa) by impairing inactivation of NaV1.6, but not the predominant cardiac NaV isoform NaV1.5. We investigated arrhythmia mechanisms using mice with cardiac-specific expression of D96V-CaM (cD96V). Super-resolution microscopy revealed close proximity of NaV1.6 and RyR2 within T-tubules. NaV1.6 density within these regions increased in cD96V relative to WT mice. Consistent with NaV1.6 dysregulation by D96V-CaM in these regions, we observed increased late NaV activity in T-tubules. The resulting late INa promoted aberrant Ca2+ release and prolonged APD in myocytes, leading to LQT and ventricular tachycardia in vivo. Cardiac-specific NaV1.6 KO protected cD96V mice from increased T-tubular late NaV activity and its arrhythmogenic consequences. In summary, we demonstrate that D96V-CaM promoted arrhythmias by dysregulating LTCCs and NaV1.6 within T-tubules and thereby facilitating aberrant Ca2+ release.

Estimation of (Co) Variance Components and Genetic Parameters for Pre- and Post-Weaning Growth Traits in Dagliç Sheep.

The goal of this study was to estimate (co) variance components and genetic parameters for pre- and post-weaning growth traits in Dagliç sheep, considering the direct additive genetic, maternal genetic, and maternal permanent environmental effects, with different statistical models. The information of 21,735 native Dagliç lambs born between 2011 and 2021 was used to estimate (co) variance components by the Average Information-Restricted Maximum Likelihood algorithm. The results showed that the most suitable model was Model 3 for birth weight (BW), average daily gain (ADG), and weaning weight (WW). Model 4 was the most appropriate for weight at three (W3), weight at six (W6), and weight at twelve months of age (W12). The direct heritabilities for BW, W3, ADG, WW, W6, and W12 were 0.35 ± 0.02, 0.36 ± 0.03, 0.27 ± 0.02, 0.22 ± 0.02, 0.47 ± 0.05, and 0.47 ± 0.05, respectively. Genetic and phenotypic correlations amongst the traits were in the range of 0.103 ± 0.008 to 0.995 ± 0.002. These results can be used for the improvement of growth traits in the Dagliç breed of sheep through selection.

The comparative results of myostatin introgression from donor Texel to recipient Ramliç sheep with the aspects of growth, pre-, and post-slaughter carcass traits in the second backcross generation.

The aim of the study was to evaluate the growth, body and ultrasonic measurements and some carcass traits of purebred Ramliç, Texel and crossbred (87.5 % Ramliç and 12.5 % Texel) lambs in a marker-assisted introgression (MAI) project. The effects of some environmental factors such as genotype, sex, birth type, dam age, weaning age, and birth weight on growth, ultrasound measurements, and carcass traits were significant ( P < 0.05 ). There were no significant differences between pure Ramliç and its myostatin carrier ( + / - ) and non-carrier ( - / - ) second backcrosses (BC 2 ) for birth weight, daily live weight gain, and weaning weight. The BC 2 genotype ( + / - ) was statistically caught up with pure Ramliç for wither height, body length, and rump width. Differences in the longissimus muscle depth indicated that the BC 2 ( + / - ) genotypes tended to be better for both pure Ramliç and Texel lambs. Texel lambs were superior to Ramliç in the aspect of some carcass characteristics such as leg length, cold right-half carcass weight, foreleg weight in the left-half carcass, and muscle weight in the left leg. BC 2 ( + / - ) lambs were in the middle of both breeds for the traits. BC 2 lambs carrying myostatin did not vary from Ramliç morphologically. The new type of Ramliç was also closer to Texel in the aspect of carcass characteristics. In this connection, improvement of indigenous breeds could be achieved by MAI without changing the essential characteristics. For the summary, please visit http://www.mustafatekerli.com (last access: 14 June 2022).

Leukocyte telomere length and lipid parameters in patients with myocardial infarction with non-obstructive coronary arteries.

Myocardial infarction with non-obstructive coronary arteries (MINOCA) is defined as stenosis of less than 50% or no stenosis on coronary angiography in a patient diagnosed with myocardial infarction. Telomere length is expressed by studies that it acts as a biomarker, especially for biological aging and cardiovascular diseases. In this study, we aimed to investigate whether there is a relationship between circulating leukocyte telomere length (LTL) and serum lipid values in MINOCA patients. Forty-five newly diagnosed patients with MINOCA were included in the study, along with 45 healthy controls who matched the patients in terms of age and gender. We determined the LTL value using the RT-PCR method. As a result of the study, we found LTL (p< 0.001) and serum lipid values (HDL-cholesterol (p< 0.001), LDL-cholesterol (p< 0.001), triglycerides (p< 0.05), and total cholesterol (p< 0.05)) to be significantly higher in the MINOCA group than in the control group. When the correlation relationship between LTL and lipid values in the MINOCA group was evaluated, a negative correlation was determined only between LTL and HDL (p=0.014, r=-0.362). This is the first study to evaluate telomere length in MINOCA patients in Turkey. Our results support the existence of short telomere length in MINOCA patients.

Prevalence of cardiac arrhythmia and risk factors in chronic kidney disease patients.

Chronic kidney disease (CKD) patients have a high risk for cardiac arrhythmia. This study aimed to investigate the prevalence of cardiac arrhythmia in CKD patients and to evaluate the relationship between arrhythmia and biochemical and echocardiographic parameters. CKD patients between 18 and 80 years of age were enrolled from the nephrology outpatient clinic. Physical examination, complete blood count, urinalysis biochemical analysis, electrocardiogram, echocardiogram, and 24-h Holter electrocardiogram were performed. Patients with and without cardiac arrhythmia were compared regarding their characteristics, laboratory findings, and echocardiographic parameters. Risk factors for cardiac arrhythmia were also evaluated. The carotid intima-media thickness was measured using Doppler ultrasonography. In our study involving 59 patients, 44 (74%) had atrial arrhythmia (AA) and 40 (68%) had ventricular arrhythmia (VA). Atrial and/or VA were diagnosed in 46 patients (78%), of whom six (10.2%) had AA, two (3.4%) had VA and 38 (64.4%) had AA plus VA. Atrial fibrillation (AF) was present in two patients (3.4%) in the form of paroxysmal AF. Risk factors for AA were low calcium level and posterior wall thickness, while factors associated with VA were age, triglyceride level, leukocyte count, and nonusage of angiotensin 2 receptor blockers. Risk factors for AA and/or VA included increased platelet count, age, and leukocyte count. AA and/or VA were found in as high as 78% of CKD patients. Further studies evaluating course of the disease from early stages are needed to identify risk factors.

The Incidence and the Risk Factors of Silent Embolic Cerebral Infarction After Coronary Angiography and Percutaneous Coronary Interventions.

Silent embolic cerebral infarction (SECI) is a major complication of coronary angiography (CAG) and percutaneous coronary intervention (PCI). Patients with stable coronary artery disease (CAD) who underwent CAG with or without PCI were recruited. Cerebral diffusion-weighted magnetic resonance imaging was performed for SECI within 24 hours. Clinical and angiographic characteristics were compared between patients with and without SECI. Silent embolic cerebral infarction occurred in 12 (12%) of the 101 patients. Age, total cholesterol, SYNTAX score (SS), and coronary artery bypass history were greater in the SECI(+) group (65 ± 10 vs 58 ± 11 years,P= .037; 223 ± 85 vs 173 ± 80 mg/dL,P= .048; 30.1 ± 2 vs 15 ± 3,P< .001; 4 [33.3%] vs 3 [3.3%],P= .005). The SECI was more common in the PCI group (8/24 vs 4/77,P= .01). On subanalysis, the SS was significantly higher in the SECI(+) patients in both the CAG and the PCI groups (29.3 ± 1.9 vs 15 ± 3,P< .01; 30.5 ± 1.9 vs 15.1 ± 3.2,P< .001, respectively). The risk of SECI after CAG and PCI increases with the complexity of CAD (represented by the SS). The SS is a predictor of the risk of SECI, a complication that should be considered more often after CAG.

Expert panel on cost analysis of atrial fibrillation.

OBJECTIVE: To estimate total cost of atrial fibrillation (AF) management concerning acute coronary syndrome, heart failure, stroke and drug related adverse events with respect to clinical practice and available guidelines. METHODS: This cost analysis study was based on identification of total costs related to management of acute coronary syndrome, heart failure, stroke and the drug related adverse events in patients with AF based on standardized questionnaire forms filled by experts according to their daily clinical practice and also to ACCF/AHA/ESC guidelines. Total cost included cost items related to treatment, healthcare resources utilization, and diagnostic test and consultations. RESULTS: The yearly cost of acute coronary syndrome per patient was 5.478.43 TL according to expert's view reflecting real clinical practice whereas it was 11.319.44 TL when calculation was based on recommendations in the guidelines. The average total cost of heart failure was 4.523.74 TL according to expert's view whereas it was 2.925.86 TL based on guidelines. The average total cost of stroke was 5.719.25 TL according to expert's view but 7.931.18 TL based on guidelines. Among drug related adverse events, only those related to cardiac adverse events were estimated to be higher according to expert view as compared to guideline recommendations (288.65 vs. 150.99 TL). CONCLUSIONS: Reflecting the treatment algorithms in the management of AF and related adverse events, our findings seem to emphasize the extra burden on health economics posed by patients suffering from the uncontrolled disease.

[The frequency of aspirin resistance by a modified thrombelastography method and its relationship with clinical and laboratory parameters in patients with stable coronary artery disease]. / Kararli koroner arter hastaligi olanlarda modifiye tromboelastogram yöntemi ile aspirin direnci sikligi ve klinik ve laboratuvar bulgularla iliskisi.

OBJECTIVES: Aspirin is the cornerstone of antiplatelet therapy in cardiovascular medicine. However, aspirin resistance has been demonstrated in 0.4% to 83.3% of aspirin-receiving patients. The aim of this study was to investigate the frequency of aspirin resistance using a modified thrombelastography (mTEG) method and related clinical and biochemical parameters in patients with stable coronary artery disease (CAD), who received 100 mg/day aspirin. STUDY DESIGN: The study included 168 patients (115 males, 53 females; mean age 60±8 years) with stable CAD, receiving aspirin at a dose of 100 mg/day. Aspirin responsiveness was determined using mTEG, where aspirin resistance was defined as arachidonic acid-induced whole blood platelet aggregation inhibition (PAI) of less than 50%. RESULTS: Aspirin resistance was detected in 27 patients (16.1%). Platelet aggregation inhibition showed negative correlations with hyperlipidemia, smoking, spironolactone use, systolic blood pressure, pulse pressure, and total cholesterol and fibrinogen levels. In multivariate regression analysis, only fibrinogen level (OR=1.063, p=0.010) and pulse pressure (OR=1.197, p=0.023) were found to be independent indicators of aspirin resistance and PAI. In ROC analysis, cut-off values of 50 mmHg for pulse pressure and 400 mg/dl for fibrinogen level predicted aspirin resistance with 88.9% and 74% sensitivity and 64.4% and 68% specificity, respectively. CONCLUSION: Our findings suggest that measurements of fibrinogen level and pulse pressure may be used as easy and reliable methods in predicting aspirin resistance.

The effect of different atrioventricular delays on left atrium and left atrial appendage function in patients with DDD pacemaker.

BACKGROUND: Although it has been known that optimization of atrioventricular delay (AVD) has favorable effect on the left ventricular functions in patients with DDD pacemaker, the effect of different AVDs on left atrium (LA) and left atrial appendage (LAA) functions has not been exactly evaluated. The aim of the present study was to assess the effect of different AVDs on LA and LAA functions in DDD pacemaker implanted patients with atrioventricular block. METHODS: Forty-eight patients with DDD pacemaker were enrolled into the study. Patients were divided into two groups according to the echocardiographic diastolic function: Group I (normal diastolic function) and Group II (diastolic dysfunction). LAA emptying velocity on pulsed wave Doppler and LAA late systolic wave velocity by using tissue Doppler were recorded. Patients were paced for five successive continuous pacing periods of 10 minutes duration using five selective AVDs (80-250 ms). RESULTS: Significant effect on LA and LAA functions has not been observed by the setting of AVD in Group I. However, when the AVD was gradually shortened form 150 ms to 80 ms, LA and LAA functions gradually decreased in Group II patients. When AVD increased to 200 ms, LA and LAA functions were improved. Further increase in AVD resulted in decreased LA and LAA functions. CONCLUSION: Setting of AVD has not significant effect on the LA and LAA functions in patients with normal diastolic function, but moderate prolongation of AVD in physiological limits improved LA and LAA functions in DDD pacemaker implanted patients with diastolic dysfunction.

The relation between serum erythropoietin level and severity of disease and mortality in patients with chronic heart failure.

OBJECTIVE: We evaluated the relation between serum erithropoietin level and the severity of disease and mortality in patients with chronic heart failure (CHF). METHODS: We enrolled 96 CHF patients and 50 age- and sex-matched control subjects. Haemoglobin, haemotocrit, N terminal pro-B type natriuretic peptide (NT-proBNP) and erythropoietin levels and echocardiographic parameters were measured. The patients were contacted 1 year after the evaluations to determine survival. RESULTS: The patients had lower haemoglobin and haematocrit but higher serum erythropoietin and NT-proBNP levels than the control subjects. Serum erythropoietin and NT-proBNP levels increased with worsening functional class. The serum erythropoietin level correlated negatively with left ventricular ejection fraction (r = -0.404, P < 0.001), haemoglobin (r = -0.530, P < 0.001) and haematocrit (r = -0.496, P < 0.001) levels. The patients who died (n = 17) had lower haemoglobin and haematocrit levels and significantly higher erythropoietin and NT-proBNP levels. However, multivariate logistic regression analysis showed that only NT-proBNP level was an independent predictor of mortality (P = 0.002). CONCLUSION: Anaemia and resistance to erythropoietin develop proportionately to disease severity and left ventricular systolic dysfunction in patients with CHF. Although serum erythropoietin level seems related with mortality, this observation needs to be confirmed by studies with more patients and longer follow-up.

Cardiac troponin T as a prognostic marker in patients with heart failure : a 3-year outcome study.

Cardiac troponin T (cTnT), a highly sensitive and specific indicator of myocardial cell death, may be elevated in congestive heart failure (CHF). The aims of this study were to test the hypothesis that decompensated CHF may be associated with an increase in cTnT release and to correlate between cTnT levels and patient outcomes. The authors studied 55 patients aged between 38 and 86 years (30 women and 25 men) who were hospitalized for CHF. Left ventricular ejection fraction (EF) was calculated by using modified Simpson's rule by echocardiography. cTnT levels were assessed. Troponin T >or=0.1 ng/mL was considered as positive. All patients were contacted by phone annually during the next 3 years, and their history of subsequent hospital admissions and current health status were recorded. cTnT was negative in 44 (80%) and positive in 11 (20%) patients. EF was significantly lower and NYHA was higher in cTnT-positive patients. During the 3-year follow-up period, 25 patients died from CHF. The mortality rate was 8/11 (72.7%) among cTnT-positive patients, whereas the mortality rate was 17/44 (38.6%) among cTnT-negative patients. There were significant relationships among positivity of cTnT, NYHA, EF, and mortality rate. Multivariate regression analysis yielded an independent relationship between positivity of cTnT, NYHA classification, and mortality rate. The percent of hospital admissions due to CHF was also higher in patients with cTnT positive (63.6% versus, 27.3%, p <0.05). In conclusion, this study shows that cTnT positivity is an independent risk factor in predicting the long-term mortality and morbidity rate in patients with CHF. Patients with worsening CHF may possibly be identified early on the basis of their elevated serum cTnT levels.

The effect of early statin treatment on inflammation and cardiac events in acute coronary syndrome patients with low-density lipoprotein cholesterol.

We investigated the effects of atorvastatin on inflammation and cardiac events during the inpatient period and initial 6-month follow-up in acute coronary syndrome (ACS) patients with low low-density lipoprotein (LDL) cholesterol level. One hundred and twelve consecutive ACS patients with LDL cholesterol less than 100 mg/dl were included in the study (mean 78.2+/-12.3 mg/dl). While 70 randomly selected patients received a dose of 40 mg atorvastatin within the first 24 h on top of their standard treatment as the atorvastatin group, the remaining 42 patients considered as the control group were given the standard treatment only, i.e., without any lipid-lowering drug therapy. Lipid profile, high-sensitivity C-reactive protein (hsCRP), and plasma amyloid A (SAA) levels were measured in all patients within the first 24 h of chest pain, on the 5th day, and in the 6th month. During the inpatient period and subsequent 6-month follow-up, all episodes of angina, reinfarction, revascularization, heart failure, rehospitalization, cardiac mortality, and total number of cardiac events were recorded. In the atorvastatin group, hsCRP and SAA values on the 5th day and in the 6th month compared to the first 24 h were significantly lower than those of the control group (P<0.0001). Mean LDL cholesterol level was significantly decreased in the atorvastatin group (55.7+/-17.7 mg/dl), but there was no significant change in the control group at the 6th month. The frequency of heart failure during the inpatient period and angina, unstable angina pectoris, heart failure, and revascularization in the first 6 months were also significantly reduced in the atorvastatin group. Atorvastatin started in the first 24 h reduces inflammation and improves the prognosis during both the inpatient period and the first 6 months of clinical follow-up in ACS patients with low LDL cholesterol levels.

The presence of a calcific plaque in the common carotid artery as a predictor of coronary atherosclerosis.

Many contradictory reports have been published investigating the relationship between coronary artery disease (CAD) and the increased intima-media thickness (IMT) in the common carotid artery (CCA). However, only a limited number of studies evaluate the relationship between CAD and CCA disease as reflected by both the plaque morphology (fibrous and calcific plaques) and IMT. We have studied the associations between CAD and the wall morphology of CCA by B-mode ultrasound (US). One hundred and forty-four subjects, whose angiography was planned on the basis of suspected CAD, were included into the study. The patients were divided into 4 groups on the basis of B-mode US findings; Group I: normal, Group II: increased IMT (IMT >/= 0.8 mm and plaque absent), Group III: fibrous plaque, Group IV: calcific plaque. Coronary artery disease was diagnosed in 63 patients. A statistically significant correlation was found between CAD and CCA wall morphology (r =0.42, CI (95%) = 0.30-0.51, p<0.001). Positive predictive values were 45.0%, 48.4%, and 75.0% in patients with increased IMT, fibrous plaque, and calcific plaque, respectively. None of the women with normal CCA wall morphology had significant coronary artery lesion. With respect to the normal group, the risk for CAD increased by 4.3 fold with the existence of fibrous plaque (p=0.02) and by 9.9 fold with the existence of calcific plaque (p<0.001). It has been shown that the CCA wall morphology determined by B-mode US is correlated with CAD in patients with chest pain, and the presence of calcific plaque is a better predictor for CAD than that of fibrous plaque and increased IMT. Women with chest pain and normal CCA wall morphology may not need coronary angiography.

'Natural Conduit' between two atria associated with atrial septal defect.

Herein, we present a case of 46 years old woman with an extracardiac venous connection between two atria associated with secundum type atrial septal defect (ASD). This interatrial tunnel was not recognized by both transthoracic and transesophageal echocardiographic examinations. Computed tomography suspected a blood flow from right inferior pulmonary vein to inferior caval vein. Consequently, the patient underwent cardiac catheterization. Angiography revealed a tunnel between left and right atrium. To our knowledge, this is the first report of a case with venous tunnel between two atria associated with secundum type ASD in the literature.

Prothrombin 20210GA and factor V Leiden mutations in patients less than 55 years old with myocardial infarction.

Several studies claim that prothrombin 20210GA and factor V Leiden mutations are related to arterial thrombosis. We investigated the frequencies of these mutations and their significance in the development of early atherosclerosis in acute myocardial infarction (AMI) patients younger than 55 years of age. We investigated 96 patients with AMI and 77 control subjects. The diagnosis of AMI was established by typical chest pain and ST elevations on the presentation electrocardiogram and characteristic cardiac enzyme elevations. None of the control subjects had evidence of cardiovascular disease. DNA samples were isolated from all subjects and prothrombin 20210GA and factor V Leiden mutations were determined by the RealTime PCR technique with the aid of a Light Cycler device. The prevalence of factor V Leiden mutation was 6.3% and 5.2% in the patient and control groups, respectively (OR 0.6 [95% CI 0.1- 3.9], P = 0.6), whereas the prevalence of prothrombin G20210A mutation was 4.2% and 2.6% in the patient and control groups, respectively (OR 2.8 [95% CI 0.2 - 32.2], P = 0.4). None of the patients had both mutations. Prothrombin 20210GA and factor V Leiden mutations are not significant risk factors for the development of myocardial infarction in patients less than 55 years old in Southern Turkey.