Identification of the pathogenic effects of missense variants causing PRKAG2 cardiomyopathy.

BACKGROUND: Pathogenic missense variants in PRKAG2, the gene for the gamma 2 regulatory subunit of adenosine monophosphate-activated protein kinase (AMPK), cause severe progressive cardiac disease and sudden cardiac death, named PRKAG2 cardiomyopathy. In our previous study, we reported a E506K variant in the PRKAG2 gene that was associated with this disease. This study aimed to functionally characterize the three missense variants (E506K, E506Q, and R531G) of PRKAG2 and determine the possible effects on AMPK activity. METHODS: The proband was clinically monitored for eight years. To investigate the functional effects of three missense variants of PRKAG2, in vitro mutagenesis experiments using HEK293 cells with wild and mutant transcripts and proteins were comparatively analyzed using quantitative RT-PCR, immunofluorescence staining, and enzyme-linked immunosorbent assay. RESULTS: In the long-term follow-up, the proband was deceased due to progressive heart failure. In the in vitro experimental studies, PRKAG2 was overexpressed after 48 h of transfection in three mutated cells, after which the expression levels of PRKAG2 were regressed to the level of wild-type cells in 3-weeks stably transformed cells, except for the cells with E506K variant. E506K, E506Q, and R531G variants had caused a reduction in the AMPK activity and resulted in the formation of cytoplasmic glycogen deposits. CONCLUSION: Three missense variants that alter AMPK activity affect a residue in the CBS4 domain associated with ATP/AMP-binding. Detailed information on the influence of PRKAG2 pathogenic variants on AMPK activity would be helpful to improve the treatment and management of patients with metabolic cardiomyopathy.

Comparison of electrophysiological characteristics of right- and left-sided Mahaim-type accessory pathways.

AIMS: Mahaim-type accessory pathways (MAPs) are generally right-sided due to the embryological differentiation, but left-sided localization is also possible. This study aims to compare the clinical and electrophysiological characteristics of right- and left-sided MAPs. METHODS: Of 251 patients diagnosed with AP by electrophysiological study between November 2015 and February 2020, 12 patients with MAP were included (right sided n = 8, left sided n = 4). MAP was diagnosed if; (1) no retrograde conduction; (2) anterograde decremental conduction; (3) adenosine sensitivity; and (4) Mahaim potential at successful ablation site were present. RESULTS: Ten of twelve MAPs were clustered on the lateral walls of the mitral (n = 3, 75%) and tricuspid annuli (n = 7, 87.5%). Right-sided MAPs were mostly long pathways extending toward the conduction system whereas left-sided MAPs were short extending toward the neighboring myocardium. For right- and left-sided APs, the median QRS times were 129 and 156 ms (p = .042), the median VAbl -RVApex intervals were -12 and 64 ms (p = .007), the median QRS-V(His) intervals were 16 and 86 ms (p = .120), and the median VAbl -QRS interval was -8 and 12 ms (p = .017), respectively. Coexistence of dual atrioventricular node physiology was observed only in right-sided APs (n = 3, 37.5%). CONCLUSION: MAPs are more typically located on the right but may rarely be seen on the left. Catheter ablation was associated with high success without complications.

Elective percutaneous coronary intervention leads to significant changes in serum resistin, leptin, and adiponectin levels regardless of periprocedural myocardial injury: an observational study.

OBJECTIVE: Bioactive roles of adipokines in coronary atherosclerosis and acute coronary syndromes have been demonstrated previously. However, there is a lack of data regarding the relationship between serum adipokines and periprocedural myocardial injury (PMI) following elective percutaneous coronary intervention (PCI). Therefore, we aimed to investigate the association between serum adipokines and PMI related to elective PCI. METHODS: In total, 153 consecutive patients (aged 60.6±8.2 years, 98 men) with stable angina pectoris undergoing elective PCI were enrolled in this observational cross-sectional study. Serum resistin, leptin, adiponectin, and high-sensitive Troponin T (hscTnT) levels were measured immediately before PCI and after 12-h PCI. The no-injury, PMI, and type 4a myocardial infarction (type 4a MI) groups were defined as groups consisting patients with post-procedural hscTnT concentrations <14 ng/L, between 14-70 ng/L, and >70 ng/L, respectively. RESULTS: Serum hscTnT, resistin, and leptin concentrations significantly (p<0.001) increased while serum adiponectin levels decreased (p<0.001) after 12-h elective PCI. However, no correlation was found between post-procedural hscTnT concentrations and resistin, leptin, and adiponectin levels. The no-injury group consisted of 65 patients (42.4%), whereas PMI and type 4a MI were observed in 70 (45.8%) and 18 (11.8%) patients, respectively. The average pre-procedural and post-procedural resistin, leptin, and adiponectin levels did not show any significant difference in the no-injury, PMI, and type 4a MI groups. CONCLUSION: There is no correlation between serum adipokine levels and post-procedural troponin elevations reflecting PMI or type 4a MI. However, serum resistin and leptin levels increase, whereas adiponectin levels decrease significantly after elective PCI.

Association between non-coding polymorphisms of HOPX gene and syncope in hypertrophic cardiomyopathy.

OBJECTIVE: Homeodomain Only Protein X (HOPX) is an unusual homeodomain protein which regulates Serum Response Factor (SRF) dependent gene expression. Due to the regulatory role of HOPX on SRF activity and the regulatory role of SRF on cardiac hypertrophy, we aimed to investigate the relationship between HOPX gene variations and hypertrophic cardiomyopathy (HCM). METHODS: In this study, designed as a case-control study, we analyzed coding and flanking non-coding regions of the HOPX gene through 67 patients with HCM and 31 healty subjects. Certain regions of the gene were investigated by Single Stranded Conformation Polymorphism (SSCP) and Restriction Fragment Length Polymorphism (RFLP). Statistical analyses of genotypes and their relationship with clinical parameters were performed by chi-square, Kruskal-Wallis and the Fisher's exact test. RESULTS: In 5' Untranslated Region (UTR) and intronic region of the HOPX gene, we found a C>T substitution and an 8-bp insertion/deletion (In/Del) polymorphism, respectively. These two polymorphisms seemed to constitute an haplotype. While the frequency of homozygous genotypes of In/Del and C/T polymorphisms were found significantly lower in the patients with syncope (p=0.014 and p=0.017, respectively), frequency of their heterozygous genotypes were found significantly higher in the patients with syncope (p=0.048 and p=0.030, respectively). CONCLUSION: Though there was not found any mutation in coding sequence of HOPX gene, two non-coding polymorphisms were found related to syncope in HCM patients. While homozygous status of these polymorphisms was found to be protective against the syncope, their heterozygous status seemed to be a risk factor for syncope in HCM patients. Our results suggest that HOPX may contribute to pathogenesis or manifestation of HCM as a modifier gene.

Verification of pulmonary vein isolation during single transseptal cryoballoon ablation: a comparison between the classical circular mapping catheter and the inner lumen mapping catheter.

AIMS: Cryoballoon ablation has proven very effective in achieving pulmonary vein isolation (PVI). The novel Achieve inner lumen mapping catheter designed to be used in conjunction with the cryoballoon, serves as both a guidewire and a mapping catheter. To our knowledge, this is the first study comparing the latter to verification of electrical isolation with the 'traditional' circular mapping catheter. METHODS AND RESULTS: We assigned 40 consecutive patients matched for age and left atrial diameter suffering of paroxysmal atrial fibrillation to cryoballoon PVI using either the circular mapping catheter or the Achieve as a mapping catheter. Duration of procedure as well as fluoroscopy times were significantly lower in the Achieve group than in the circular mapping catheter group (111 ± 14 min vs. 126 ± 13 min, P < 0.005 and 22 ± 5 min vs. 29 ± 4 min, P < 0.0001, respectively). There were no significant differences between both groups in terms of mean degree of occlusion, mean minimal temperatures, and PVI. Pulmonary vein isolation could be documented by real-time recordings in 55% of veins in the Achieve group with mean time to isolation of 65 ± 23 s. CONCLUSION: Cryoballoon ablation in conjunction with the novel Achieve is feasible, safe, and affords PVI in nearly all veins in similar proportions to the approach with the traditional guidewire. Furthermore, if compared to the procedure with the circular mapping catheter, cryoballoon ablation with the Achieve is significantly faster and associated to shorter fluoroscopy times.

Pulmonary vein isolation during cryoballoon ablation using the novel Achieve inner lumen mapping catheter: a feasibility study.

AIMS: Cryoballoon (CB) ablation has proven very effective in achieving pulmonary vein isolation (PVI). The Achieve catheter (AC) is a novel inner lumen catheter designed to be used in conjunction with the CB, which serves the double purpose of a guidewire and a mapping catheter. We aimed to evaluate the feasibility of CB ablation in conjunction with the novel AC, in terms of PVI and safety in a series of patients affected by drug resistant paroxysmal atrial fibrillation (AF). METHODS AND RESULTS: Seventy patients (49 male) affected by paroxysmal AF were assigned to CB PVI using the AC as a mapping catheter. Patients underwent loop-Holter monitoring 1, 3 and 6 months after ablation. Isolation occurred in 98% of PVs with the CB-AC association without having switching to a regular guidewire. Pulmonary vein isolation could be documented by real-time (RT) recordings in 47% (132) of veins. Time to isolation was significantly longer in PVs exhibiting early left atrium-PV reconnection if compared with veins with sustained isolation (117 ± 25 s vs. 59 ± 25 s; P< 0,005). No serious complications occurred; four transient phrenic nerve palsies occurred all resolving completely before the end of the procedure. CONCLUSION: Cryoballoon ablation in conjunction with the novel AC is feasible, safe, and most importantly affords PVI in nearly all veins without having to switch to a regular guidewire. However, RT recordings could be documented in only 47% of pulmonary veins.

Isolating the pulmonary veins as first-line therapy in patients with lone paroxysmal atrial fibrillation using the cryoballoon.

AIMS: Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. Nowadays, catheter-based ablative approaches are mainly reserved for drug-refractory patients. However, the value of an ablative therapy as a first-line alternative remains elusive. The aim of our study was to analyse the acute procedural success and clinical outcome of patients with lone paroxysmal AF undergoing cryoballoon ablation (CBA) as first-line treatment. METHODS AND RESULTS: Eighteen individuals (mean age 44 ± 9 years, range 23-61 years, 15 males) with lone paroxysmal AF preferring a catheter-based treatment to drug treatment as first-line therapy were consecutively enrolled in our study. Mean left atrial size was 39 ± 4 mm and mean left ventricular ejection fraction 58 ± 3%. After a mean of 2.4 CBA (range 2-4) applications pulmonary vein (PV) isolation could be demonstrated in 70 (97%) PVs. Additional lesions with a focal ablation catheter were needed to isolate one right inferior pulmonary vein and one left superior pulmonary vein in two different patients. At the end of the procedure, all (100%) PVs were isolated. After a 2-month blanking period, 16 patients (89%) were free of symptomatic AF recurrence at a mean follow-up of 14 ± 9 months and without antiarrhythmic drugs (AADs). CONCLUSION: Cryoballoon ablation in patients with lone paroxysmal AF yields a high acute efficacy rate with a great chance of being free of symptomatic AF recurrence without antiarrhythmic drugs on a mid-term follow-up period, when offered as a first-line treatment.

Value of electrocardiogram in the differentiation of hypertensive heart disease, hypertrophic cardiomyopathy, aortic stenosis, amyloidosis, and Fabry disease.

Left ventricular hypertrophy is 1 of the most frequent cardiac manifestations associated with an unfavorable prognosis. However, many different causes of left ventricular hypertrophy exist. The aim of the present study was to assess the diagnostic value of common electrocardiographic (ECG) parameters to differentiate Fabry disease (FD), amyloidosis, and nonobstructive hypertrophic cardiomyopathy (HC) from hypertensive heart disease (HHD) and aortic stenosis (AS). In 94 patients with newly diagnosed FD (n = 17), HHD (n = 20), amyloidosis (n = 17), AS (n = 20), and HC (n = 20), common ECG parameters were analyzed and tested for their diagnostic value. A stepwise approach including the Sokolow-Lyon index, corrected QT duration, and PQ interval minus P-wave duration in lead II to overcome P-wave abnormalities was applied. A corrected QT duration <440 ms in combination with a PQ interval minus P-wave duration in lead II <40 ms was 100% sensitive and 99% specific for the diagnosis of FD, whereas a corrected QT duration >440 ms and a Sokolow-Lyon index ≤1.5 mV were found to have a sensitivity and specificity of 85% and 100%, respectively, for the diagnosis of amyloidosis and differentiation from HC, AS, and HHD. Moreover, a novel index ([PQ interval minus P-wave duration in lead II multiplied by corrected QT duration]/Sokolow-Lyon index) proved to be highly diagnostic for the differentiation of amyloidosis (area under the curve 0.92) and FD (area under the curve 0.91) by receiver operator characteristic analysis. In conclusion, a combined analysis of PQ interval minus P-wave duration in lead II, corrected QT duration, and Sokolow-Lyon index proved highly sensitive and specific in the differentiation of FD, amyloidosis, and HC compared to HHD and AS. Analysis of these easy-to-assess ECG parameters may be of substantial help in the diagnostic workup of these 5 conditions.

Pulmonary vein ostium shape and orientation as possible predictors of occlusion in patients with drug-refractory paroxysmal atrial fibrillation undergoing cryoballoon ablation.

AIMS: No specific data are available on the influence of pulmonary vein (PV) anatomy and shape on cryoballoon ablation (CA) catheter efficacy in delivering cryothermal energy and, consequently, in obtaining PV isolation. METHODS AND RESULTS: Among a larger series of patients (68) with drug-refractory paroxysmal atrial fibrillation who underwent CA in our department, 52 patients were included in our study. All of them had a multislice cardiac computed tomography (MSCT) before the procedure. We retrospectively evaluated their MSCT scans focusing our attention on PV ovality and orientation in the frontal plane. A fair inverse association was documented between the ovality index of the left PVs and the degree of occlusion (r=-0.486 and P<0.003 for the LSPV and r=-0.360 and P=0.033 for the LIPV), whereas no association was found between the ovality index of the right PVs and the degree of occlusion (r=-0.283 and P=0.083 for the RSPV and r=0.235 and P=0.093 for RIPV). Nevertheless, a strong inverse association was found between the orientation of the PV ostia and the degree of occlusion in each vein (r=-0.804 and P<0.001 for the LSPV, r=-0.415 and P=0.013 for LIPV, r=-0.798 and P<0.001 for the RSPV, and r=-0.867 and P<0.001 for RIPV). CONCLUSION: Pulmonary vein ostium shape and orientation evaluated by MSCT proved to be useful in predicting the degree of occlusion obtained during CA.

Evaluation of myocardial bridges with 64-slice computed tomography coronary angiography.

OBJECTIVE: The aim of this study is to report the characteristics of myocardial bridging (MB) using 64-slice computed tomography and to demonstrate the association between atherosclerotic coronary artery disease (CAD) and MB. METHODS AND RESULTS: In 990 consecutive patients who underwent multi-slice computed tomography (MSCT) coronary angiography for suspected or known coronary artery disease, myocardial bridge evaluation was performed with axial, curved multiplanar reconstruction and three-dimensional volume-rendered images. 265 bridged segments were identified in 223 (22.5%) patients. Multiple MBs on left coronary arteries were found in 41 patients. Most of the MBs were in the LAD (62.6%), followed by the obtuse marginal artery (14.7%) and diagonal artery (14.3%). The average length of MBs was 14 +/- 7 mm, and the average depth was 1.6 +/- 11 mm. No significant difference was observed between patients with and without MB on the middle LAD in respect of age, gender, prevalence of diabetes, hyperlipidaemia, hypertension, current smoking and prevalence of atherosclerotic plaques at the proximal LAD. On the other hand, prevalence of atherosclerotic plaques at the distal LAD were significantly lower in patients with MB on the middle LAD (3.5% vs. 19.7%, P: 0.0001). CONCLUSIONS: The presence and morphological characteristics of MB and its relation with atherosclerotic plaques in the involved coronary artery can be comprehensively analysed with 64-slice computed tomography coronary angiography. Atherosclerosis is a common finding in segments proximal to MB, but the prevalence of plaques in equivalent segments (proximal LAD in our study) is not higher than in patients under similar coronary artery disease risk and without MB. On the other hand, prevalence of atherosclerotic plaques at the distal LAD was significantly lower in our patients with MB on the middle LAD. Finally, we suggest that rather than causing proximal atherosclerosis, MB might have a more important role in the protection of distal segments of the bridged arteries from atherosclerosis.

Chronic cigarette smoking affects left and right ventricular long-axis function in healthy young subjects: a Doppler myocardial imaging study.

OBJECTIVE: Cigarette smoking is one of the major risk factors for coronary artery disease. However, chronic smoking has additional cardiac adverse effects independent of coronary atherosclerosis. We assessed the possible effects of chronic smoking on left and right ventricular (LV, RV) long-axis function using Doppler myocardial imaging (DMI). METHODS: Forty otherwise healthy smokers (mean age = 26+/-3 years) and 40 age-matched nonsmoking controls enrolled. Standard echocardiography protocol was followed by DMI. Peak systolic (V(S)), early (V(E)) and late diastolic (V(A)) velocities, peak systolic strain (S), and strain rate (SR) were measured from septal, lateral, and RV free walls. RESULTS: The baseline characteristics of two groups were similar. There were significant differences regarding Doppler myocardial velocity, S, and SR indices. Septal V(E) (P < 0.04), S (P < 0.0001) and SR (P < 0.02) were significantly reduced in smokers. For both lateral and RV free wall, V(S) (P < 0.003, P < 0.002, respectively), V(E) (P < 0.0001, P < 0.002, respectively), S (P < 0.0001 for both), and SR (P < 0.0001, P < 0.002, respectively) were significantly reduced in smokers. There were significant correlations between the amount of smoking and septal, lateral, and RV free wall S and SR. CONCLUSIONS: Chronic cigarette smoking causes alterations in long-axis systolic and diastolic functions of right and left ventricles in healthy young subjects. These changes can be accurately detected with Doppler myocardial velocity and SR imaging.

Prevalence of coronary artery disease in low to moderate-risk asymptomatic women: a multislice computed tomography study.

OBJECTIVES: Traditional risk factors may underestimate the burden of subclinical atherosclerosis in women. Recently, multislice computed tomography (MSCT) has become widely available in detecting early coronary artery disease (CAD). We sought the prevalence of CAD in low to moderate-risk asymptomatic women by MSCT coronary artery calcium (CAC) scoring and coronary angiography. STUDY DESIGN: The study included 185 women (mean age 57+/-12 years) without known CAD and diabetes, with low or moderate risk for CAD based on traditional risk scoring. Coronary artery calcium scoring and coronary angiography were performed by MSCT, which included a segment-based plaque detection and characterization of calcification. The plaques were classified based on the luminal stenotic effect (>50%). Patients with = or >1 stenotic plaque were classified as having obstructive CAD. Angiographic findings were compared with calcium scores. RESULTS: Coronary artery calcium scoring and coronary angiography detected CAD in 63 (34.1%) and 100 (54.1%) women, respectively. In both groups, women were significantly older and had higher prevalences of hypertension and dyslipidemia. Coronary angiography showed CAD in 41 women (41%; 14.6% were obstructive) without CAC. These women were significantly younger than those with a positive CAC score (p<0.01). Age (p<0.02) and hypertension (p<0.05) were found as independent predictors of CAD detected by coronary angiography. CONCLUSION: Multislice computed tomography identified a subset of low-risk women who might be at higher risk than that suggested by current risk stratification strategies. Women, especially having hypertension and dyslipidemia may be potential candidates for further risk stratification by MSCT coronary angiography.

Prognostic value of N-terminal pro-B-type natriuretic peptide in patients with active infective endocarditis.

Our aim was to determine whether N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) and cardiac troponin I (cTnI) levels are valuable for predicting prognosis in patients with infective endocarditis (IE). We analyzed measured plasma NT-pro-BNP levels at admission in 45 patients with definite IE. The primary end point was early surgery or in-hospital death. The other data recorded were baseline clinical, echocardiographic, and laboratory parameters. Thirty patients underwent early surgery, and 9 died in hospital. Univariate analysis revealed that log NT-pro-BNP, cTnI > or =0.03 ng/ml, New York Heart Association functional class III to IV symptoms, left atrial diameter, left ventricular end-diastolic diameter, left ventricular end-systolic diameter, and severe valvular regurgitation were associated with increased risk of reaching the primary end point. Cox proportional hazard regression analysis identified log NT-pro-BNP (hazard ratio 1.5; 95% confidence interval 1.2 to 1.9, p <0.001) as the only independent predictor of the primary end point. The log NT-pro-BNP cut-off value with the highest sensitivity (97%) and specificity (92%) for predicting primary end point was 7.2 (1,500 pg/ml). Patients with NT-pro-BNP level > or =1,500 pg/ml had significantly lower event-free survival than others. In conclusion, admission NT-pro-BNP is of prognostic value in patients with IE. The combination of admission NT-pro-BNP and cTnI levels appears to have even greater value for risk stratification in this patient group.

Large mural vegetation attached to the left ventricular outflow tract: a case report.

We describe an unusual case of staphylococcal endocarditis with vegetation attached to the left ventricular outflow endocardium in a patient with chronic severe aortic regurgitation that was diagnosed by transthoracic echocardiography. There was no involvement of aortic valve endocardium confirmed by transthoracic echocardiography, transesophageal echocardiography, and macroscopically in the operation. This report confirms that chronic endocardial trauma may provide a fertile nidus for the development of bacterial vegetation.