Assessment of Plaque Characteristics by Contrast-Enhanced Ultrasound and Stent Restenosis following Carotid Artery Stenting: A Retrospective Study.

Background and objective: carotid artery stenosis contributes significantly to ischemic strokes, with management options including carotid endarterectomy (CEA) and carotid artery stenting (CAS) ischemic stroke risk can be reduced. Controversies persist regarding their efficacy and factors influencing complications, and understanding the relationship between atherosclerotic plaque characteristics and stent restenosis after CAS is crucial. Methods: we conducted a retrospective study involving 221 patients who underwent CAS for symptomatic or asymptomatic carotid artery stenosis. Comprehensive assessments of plaque morphology were performed using contrast-enhanced ultrasound (CEUS) before CAS. Patient demographics, including smoking status and diabetes, were also recorded. Stent restenosis was diagnosed using various imaging modalities, including ultrasound, angiography, and digital subtraction angiography (DSA). Results: plaque analysis using CEUS revealed a significant association between plaque grade and restenosis incidence (p < 0.001), particularly with grade 0 (11.1%) and grade 2 plaques (66.7%). Smoking was notably associated with plaque vascularization and restenosis (p < 0.001), while diabetes did not significantly impact plaque characteristics or restenosis risk (p > 0.05). The mean duration of restenosis was 17.67 months. Stenting was the most frequent treatment modality for restenosis (70.6%). However, no significant relationship was found between restenosis type and plaque morphology (p = 0.268). Furthermore, while no clear relationship was observed between plaque morphology and the type of restenosis, our findings underscored the importance of plaque characterization in predicting post-CAS outcomes. Conclusions: this study highlights the utility of CEUS in predicting stent restenosis following CAS. There was a significant association between stent restenosis within 12-24 months after the carotid stenting procedure and an elevated grade of plaque vascularization. Moreover, one of the main factors possibly determining the grade of plaque vascularization was smoking. Further research is warranted to elucidate the underlying mechanisms and refine risk stratification in this patient population.

One-year initial efficacy and safety outcomes of the premounted dry-pericardium Vienna self-expandable transcatheter aortic valve system: A first-in-human VIVA feasibility study.

BACKGROUND: The dry-pericardium Vienna transcatheter aortic valve system is repositionable and retrievable, already premounted on the delivery system, eliminating the need for assembly and crimping of the device before valve implantation. METHODS: The VIVA first-in-human feasibility study, a prospective, nonrandomized, single-center trial, evaluated the Vienna aortic valve in 10 patients with severe symptomatic aortic stenosis, who were at intermediate or high surgical risk. This study, registered at ClinicalTrials.gov (NCT04861805), focused on the safety, feasibility, clinical and hemodynamic performance of the Vienna system up to 1-year follow-up. RESULTS: The mean patient age was 79 ± 5 years, 60% male. Valve sizes used: 26 mm (10%), 29 mm (30%), 31 mm (60%). Key hemodynamic improvements were significant: mean aortic valve pressure gradient (mmHg) decreased from 48.7 to 8.1, aortic valve area (cm2) increased from 0.75 to 1.91, and maximum jet velocity through the aortic valve (m/s) decreased from 4.41 to 1.95 (p < 0.0001). No moderate/severe paravalvular leakage was observed, and computed tomography scans revealed no evidence of hypo-attenuated leaflet thickening. The study recorded one life-threatening bleeding event, two cases requiring postprocedural pacemaker implantation, and three ischemic events, with only one causing lasting neurological impairment. Importantly, there were no cases of cardiovascular mortality and only one noncardiovascular death, which was confirmed as unrelated to the device. CONCLUSIONS: The study indicates the Vienna valve as a potential option for severe symptomatic aortic stenosis, designed to streamline the procedure and potentially lower healthcare costs by reducing resource and equipment needs, also procedural errors. Further research is essential to thoroughly evaluate its safety and efficacy.

Assessment of atherosclerotic plaque morphology using contrast-enhanced ultrasound and its impact on primary cardiovascular events following simultaneous carotid endarterectomy and coronary artery bypass grafting.

OBJECTIVE: The incidence of stroke after on-pump cardiac surgery during the perioperative period can affect up to 2% of patients, and is frequently linked to carotid artery disease. Notably, in patients with significant unilateral carotid artery stenosis of 80%-99%, the risk of stroke reaches 4%. Among individuals undergoing coronary artery bypass grafting (CABG), 3% to 10% exhibit significant carotid artery stenosis. To mitigate the risk of stroke and mortality, patients can undergo either simultaneous or staged carotid endarterectomy and CABG. The aim of this study was to assess whether early postoperative complications, including stroke, following simultaneous CABG/CAE procedures, correlate with morphological attributes of carotid plaque, assessed via contrast-enhanced ultrasound. METHODS: A single centre retrospective analysis was performed including 62 patients who underwent simultaneous CABG/CEA between 2019 and 2022. Our study excluded patients who underwent staged carotid endarterectomy and CABG procedures, off-pump CABG, or those necessitating urgent CABG. Our analysis focused on patients meeting elective CABG criteria, diagnosed with symptomatic triple-vessel or left main trunk coronary artery disease (CAD), alongside asymptomatic carotid stenosis (a. carotis internae) exceeding 70% or symptomatic ipsilateral carotid stenosis surpassing 50%. The extent of contralateral carotid artery stenosis was not taken into account. Prior to the CEA/CABG procedure, each patient underwent contrast-enhanced ultrasound to assess atherosclerotic lesions, which were classified using Nakamura et al.'s classification. Among the patients, 37.1% exhibited no neovascularisation within the atherosclerotic plaque, 56.5% showed insignificant neovascularisation, and 6.5% displayed notable neovascularization within the plaque. Our study aimed to establish a connection between the degree of plaque vascularisation identified through contrast-enhanced ultrasound and subsequent postoperative complications. RESULTS: Upon evaluating postoperative complications occurring within 30 days after the surgery and the plaque morphology identified through contrast-enhanced ultrasound, a statistically significant correlation was observed between a higher grade of plaque vascularisation and the occurrence of ischaemic stroke (r = 0.329, p = .008). Monte Carlo calculations of the Chi-square test indicated a significant association between a higher grade of plaque vascularisation and the presence of peripheral artery disease (χ2 = 15.175, lls = 2, p = .003). CONCLUSION: Within 30 days of surgery, a significant correlation exists between the occurrence of ischaemic stroke following carotid endarterectomy subsequent to CABG and the presence of a higher grade plaque vascularisation as identified by contrast-enhanced ultrasound.

Acquired Cardiovascular Diseases in Patients with Pulmonary Hypertension Due to Congenital Heart Disease: A Case Report.

Background: Advances in the diagnosis and treatment of congenital heart diseases (CHDs) have resulted in improved survival rates for CHD patients. Up to 90% of individuals with mild CHD and 40% with complex CHD now reach the age of 60. Previous studies have indicated an elevated risk of atherosclerotic cardiovascular disease (ASCVD) and associated risk factors, morbidity, and mortality in adults with congenital heart disease (ACHD). However, there were no comprehensive guidelines for the prevention and management of acquired cardiovascular diseases (CVDs) in ACHD populations until recently. Case presentation: A 55-year-old man with Eisenmenger syndrome and comorbidities (arterial hypertension, heart failure, dyslipidemia, hyperuricemia, and a history of pulmonary embolism (PE)) presented with progressive breathlessness. The electrocardiogram (ECG) revealed signs of right ventricle (RV) hypertrophy and overload, while echocardiography showed reduced RV function, RV overload, and severe pulmonary hypertension (PH) signs, and preserved left ventricle (LV) function. After ruling out a new PE episode, acute coronary syndrome (ACS) was diagnosed, and percutaneous intervention was performed within 24-48 h of admission. Conclusions: This case highlights the importance of increased awareness of acquired heart diseases in patients with pulmonary hypertension due to CHD.

The Effect of Platelet Activity, ABCB1 Genetic Polymorphism, and Renal Function on the Development of Ticagrelor-Related Dyspnea in Patients with Acute Coronary Syndrome.

Purpose: The aim of this study was to determine the effect of ABCB1 genetic polymorphism and renal function on the occurrence of ticagrelor-related dyspnea. Patients and Methods: A total of 299 patients with acute with type 1, 2, or 3 myocardial infarction (with and without ST-segment elevation), who underwent coronary angiography and PTCA with stent implantation and were treated with antiplatelet drugs (ticagrelor and aspirin), were enrolled in this prospective study. For all enrolled patient's platelet aggregation (induction with high-sensitivity adenosine diphosphate, ADP HS) testing was performed using a MULTIPLATE® analyzer. Venous blood was also collected for genotyping. Results: Patients experiencing ticagrelor-related dyspnea had lower ADP HS value (ADP HS ≤ 19.5 U; OR = 2.254; P = 0.009), higher creatinine concentration (>90 µmol/l; OR = 3.414; P = 0.019), and lower GFR value (<60 mL/min/1.73 m2; OR = 2.211; P = 0.035). ABCB1 T allele was associated with ticagrelor-related dyspnea (OR = 2.550; P = 0.04). Conclusion: Ticagrelor-related dyspnea was found to be related to low platelet aggregation, increased plasma creatinine concentration, decreased GFR, and ABCB1 T allele. Carriers of the ABCB1 T allele had a higher plasma creatinine concentration that could be associated with an inhibitory effect of ticagrelor on P-glycoprotein function.

Potential Prognostic Relevance of Left-Ventricular Global Longitudinal Strain and of the Summation of the Mitral and Tricuspid Regurgitation Volume in Patients with Non-Ischemic Dilated Cardiomyopathy.

BACKGROUND: The aim of this pilot study was to determine the potential prognostic relevance of novel multidirectional myocardial and volumetric echocardiographic parameters in patients with non-ischemic dilated cardiomyopathy (NIDCM). METHODS: Multidirectional myocardial parameters (longitudinal, radial, and circumferential left-ventricular (LV) strain using speckle tracking echocardiography) and a new volumetric parameter (the sum of the mitral and tricuspid regurgitation volume (mitral-tricuspid regurgitation volume) were assessed. The cardiovascular (CV) outcome was a composite of cardiac death and hospitalization for heart failure (HF) at 1 year. RESULTS: Approximately 102 patients were included in this pilot study. The mean LV ejection fraction (LVEF) was 28.4 ± 8.9%. During a follow-up of 1 year, the CV outcome occurred in 39 patients (10 HF deaths, and 36 hospitalizations for HF). The LV global longitudinal systolic strain (GLS) and mitral-tricuspid regurgitation volume were the main parameters that were seen to be significantly altered in the comparison of patients with events vs. those without events (GLS (absolute values) 7.4 ± 2.7% vs. 10.3 ± 2.6%; mitral-tricuspid regurgitation volume 61.1 ± 20.4 mL vs. 40.9 ± 22.9 mL, respectively; p-value < 0.01). In line with these findings, in a multivariate continuous logistic regression analysis, the GLS and mitral-tricuspid regurgitation volume were the main parameters associated with worse CV outcomes (GLS: OR 0.77 (95%CI 0.65-0.92); mitral-tricuspid regurgitation volume OR 1.09 (95%CI 1.01-1.25)), whereas the radial and circumferential LV global strain and mitral regurgitation volume and tricuspid regurgitation volume were not linked to the CV outcome. Furthermore, in a receiver operating characteristic curve analysis, a GLS cutoff of <7.5% and mitral-tricuspid regurgitation volume > 60 mL were the identified values for the parameters associated with worse CV outcomes. CONCLUSIONS: The findings of this pilot study suggest that the GLS and a novel volumetric parameter (the sum of the mitral and tricuspid regurgitation volume) are linked to worse CV outcomes in patients with non-ischemic dilated cardiomyopathy. Hence, these promising results warrant further validation in larger studies.

The Impact of Polymorphisms in ATP-Binding Cassette Transporter Genes on Anthracycline-Induced Early Cardiotoxicity in Patients with Breast Cancer.

BACKGROUND: Cardiac side effects associated with anthracycline-based treatment may seriously compromise the prognosis of patients with breast cancer (BC). Evidence shows that genes that operate in drug metabolism can influence the risk of anthracycline-induced cardiotoxicity (AIC). ATP-binding cassette (ABC) transporters could serve as one of the potential biomarkers for AIC risk stratification. We aimed to determine the link between single-nucleotide polymorphisms (SNPs) in several ABC genes (ABCB1 rs1045642, ABCC1 rs4148350, ABCC1 rs3743527) and cardiotoxicity. METHODS: The study included 71 patients with BC, who were treated with doxorubicin-based chemotherapy. Two-dimensional echocardiography and speckle-tracking echocardiography were performed. AIC was defined as a new decrease of 10 percentage points in the left ventricular ejection fraction (LVEF). SNPs in ABCB1 and ABCC1 genes were evaluated using real-time PCR. RESULTS: After a cumulative dose of 236.70 mg/m2 of doxorubicin, 28.2% patients met the criteria of AIC. Patients who developed AIC had a larger impairment in left ventricular systolic function compared to those who did not develop AIC (LVEF: 50.20 ± 2.38% vs. 55.41 ± 1.13%, p < 0.001; global longitudinal strain: -17.03 ± 0.52% vs. -18.40 ± 0.88%, p < 0.001). The ABCC1 rs4148350 TG genotype was associated with higher rates of cardiotoxicity (TG vs. GG OR = 8.000, 95% CI = 1.405-45.547, p = 0.019). CONCLUSIONS: The study showed that ABCC1 rs4148350 is associated with AIC and could be a potential biomarker to assess the risk of treatment side effects in patients with BC.

Relationships of Whole-Heart Myocardial Mechanics and Cardiac Morphometrics by Transthoracic Echocardiography with Main Prognostic Factors of Heart Failure in Non-Ischemic Dilated Cardiomyopathy.

BACKGROUND: there are many prognostic factors of heart failure (HF) based on their evaluation from imaging, to laboratory tests. In clinical practice, it is crucial to use widely available, cheap, and easy-to-use prognostic factors, such as left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) functional class, 6 min walk test (6MWT), B-type natriuretic peptide (BNP), etc. We sought to evaluate the relationships between whole-heart myocardial mechanics and cardiac morphometrics with the main commonly used prognostic factors of HF in patients with non-ischemic dilated cardiomyopathy (NIDCM). METHODS AND RESULTS: two-dimensional (2D) echocardiography for myocardial mechanics (global longitudinal, radial, and circumferential strains of the left ventricle; right ventricular longitudinal strain; strain values of reservoir, conduit, and contraction function of both atria) and cardiac morphometric (diameters and volumes of both atria and ventricles) parameters were performed, and the HF main traditional prognostic factors were identified. We assessed 109 patients (68.8% male; 49.7 ± 10.5 years) with newly diagnosed NIDCM. Myocardial mechanics and morphometrics were weakly correlated with the patient's age, gender, and smoking (R = 0.2, p < 0.05). Stronger relationships were observed with NYHA class, 6MWT, and BNP (the strongest correlations were with LVEF: R = -0.499, R 0.462, R = -0.461, p < 0.001, respectively). There were moderately strong correlations with LVEF and other whole-heart myocardial mechanics or morphometrics. Moreover, LVEF with global regurgitation volume (GRV) and right ventricle free wall longitudinal strain (RVFWLS) were the most usually detected parameters in multivariate analysis to be associated with changes in HF prognostic factors. CONCLUSIONS: in NIDCM patients, the main prognostic factors of HF are correlated with whole-heart myocardial mechanics and morphometrics. However, LVEF, GRV, and RVFWLS are the most usually found 2D echocardiographic factors associated with changes in HF prognostic factors.

Evaluation of Satisfaction with Healthcare Services in Multimorbid Patients Using PACIC+ Questionnaire: A Cross-Sectional Study.

Background and Objectives: Although multimorbidity poses many challenges for both individuals and healthcare systems, information on how these patients assess the quality of their healthcare is lacking. This study assessed the multimorbid patients' satisfaction with their healthcare. Materials and Methods: This cross-sectional study was a part of a project Joint Action-Chronic Diseases and Promoting Healthy Ageing across the Life Cycle and its implementation. The study included 400 patients with arterial hypertension and at least one concomitant chronic disease. Patients completed The Patient Assessment of Care for Chronic Conditions Plus (PACIC+) questionnaire, EuroQol Five-Dimensions-Three-Level Quality of Life questionnaire, and Hospital Anxiety and Depression scale. Results: The mean age of the participants was 65.38 years; there were 52.5% women. The mean PACIC+ 5As summary score was 3.60. With increasing age, participants rated worse on most PACIC+ subscales. Participants who assessed their quality of life as worse were also less satisfied with their healthcare. The presence of three or more concomitant diseases negatively affected PACIC+ scores. Patients with ischemic heart disease and heart failure had lower PACIC+ scores on most subscales, whereas patients with atrial fibrillation had lower scores only on the Agree subscale. The presence of diabetes was not associated with worse PACIC+ scores; moreover, the scores in Assist and Arrange subscales were even better in diabetic patients (3.36 vs. 2.80, p = 0.000 and 3.69 vs. 3.13, p = 0.008, respectively). Patients with chronic obstructive pulmonary disease, asthma, and musculoskeletal disorders showed lower PACIC+ scores. Conclusions: Older age, worse self-assessed health state, presence of three or more diseases, and certain chronic diseases were associated with lower patients' satisfaction with their healthcare. Personalized healthcare, increasing competencies of primary healthcare teams, healthcare services accessibility, and financial motivation of healthcare providers may increase multimorbid patients' satisfaction with their healthcare.

Instantaneous wave free ratio value impact on left internal mammary artery graft patency.

OBJECTIVES: To assess whether instantaneous wave - free ratio (iFR) value is associated with left internal mammary artery (LIMA) graft failure at 12 months follow-up post coronary artery bypass graft (CABG). BACKGROUND: Data suggests bypass to a non-significant left anterior descending artery (LAD) lesion due to visual over-estimation may lead to LIMA graft failure. Implementing iFR may result in better arterial graft patency. METHODS: In iCABG (iFR guided CABG) study patients planned to undergo an isolated CABG procedure was prospectively enrolled and iFR was performed for LAD. Coronary computed tomography angiography was performed at 2 and 12 months follow-up. The primary endpoint of this study was to determine the rate of LIMA graft occlusion or hypoperfusion at 2 and 12-months follow-up. We considered a composite secondary endpoint of Major adverse cardiovascular and cerebrovascular event (MACCE) as a secondary outcome. RESULTS: In total 69 patients were included with no differences regarding age, sex and risk factors. At 2 months, 50 of LIMAs with pre-CABG iFR median 0.855 (0.785 - 0.892) were patent. Hypoperfusion was found in 8 LIMAs (median iFR 0.88 (0.842 - 0.90)). While, 7 LIMAs (median iFR 0.91 (0.88 - 0.96)) were occluded (p = 0.04). At 12 months, when iFR of LAD was >0.85: just 12 (31.6% out of all patent LIMAS) grafts were patent and 24 (100.0% out of all hypoperfused/occluded) grafts were hypoperfused or occluded (p < 0.001). In terms of MACCE, no difference (p = 1.0) was found between all 3 groups divided according to iFR value. CONCLUSIONS: Instantaneous wave - free ratio value above 0.85 in LAD is a powerful tool predicting LIMA graft failure at 1-year follow up period.

Association of Whole-Heart Myocardial Mechanics by Transthoracic Echocardiography with Presence of Late Gadolinium Enhancement by CMR in Non-Ischemic Dilated Cardiomyopathy.

Background: In patients with non-ischemic dilated cardiomyopathy (NIDCM), myocardial fibrosis (MF) is related to adverse cardiovascular outcomes. The purpose of this study was to evaluate the potential relationship between the myocardial mechanics of different chambers of the heart and the presence of MF and to determine the accuracy of the whole-heart myocardial strain parameters to predict MF in patients with NIDCM. Methods: We studied 101 patients (64% male; 50 ± 11 years) with a first-time diagnosis of NIDCM who were referred for a clinical cardiovascular magnetic resonance (CMR) and speckle tracking 2D echocardiography examination. We analyzed MF by late gadolinium enhancement (LGE), and the whole-heart myocardial mechanics were assessed by speckle tracking. The presence of MF was related to worse strain parameters in both ventricles and atria. The strongest correlations were found between MF and left ventricle (LV) global longitudinal strain (GLS) (r = −0.586, p < 0.001), global circumferential strain (GCS) (r = −0.609, p < 0.001), LV ejection fraction (LVEF) (r = 0.662, p < 0.001), and left atrial strain during the reservoir phase (LASr) (r = 0.588, p < 0.001). However, the binary logistic regression analysis revealed that only LV GLS, GCS, and LASr were independently associated with the presence of MF (area under the curves of 0.84, 0.85, and 0.64, respectively). None of the echocardiographic parameters correlated with fibrosis localization. Conclusions: In NIDCM patients, MF is correlated with reduced mechanical parameters in both ventricles and atria. LV GLS, LASr, and LV GCS are the most accurate 2D echocardiography predictive factors for the presence of MF.

Artificial intelligence for automated evaluation of aortic measurements in 2D echocardiography: Feasibility, accuracy, and reproducibility.

AIMS: This study sought to examine the feasibility, accuracy and reproducibility of a novel, fully automated 2D transthoracic echocardiography (2D TTE) parasternal long axis (PLAX) view aortic measurements quantification software compared to board-certified cardiologists in controlled clinical setting. METHODS AND RESULTS: Aortic Annulus (AoA), Aortic Sinus (AoS), Sinotubular Junction (STJ) and Proximal Ascending Aorta (AAo) diameter measurements were performed retrospectively on each of 58 subjects in two different ways: twice using a fully automated software (Ligence Heart version 2) and twice manually by three cardiologists (ORG) and one expert cardiologist (EC). Out of 58 studies AoA was measured in 54 (93%), AoS in 55 (95%), STJ in 55 (95%) and AAo in 54 (93%) studies. Automated measurements had a stronger correlation with EC when compared to ORG with the largest correlation difference of .1 for STJ measurements and lowest difference of .01 for AoS measurements. Automated software was in higher agreement with ground truth intervals (ORG measurements mean +- SEM) in three out of four measurements. CONCLUSION: Fully automated 2D TTE PLAX view aortic measurements using a novel AI-based quantification software are feasible and yield results that are in close agreement with what experienced readers measure manually while providing better reproducibility. This approach may prove to have important clinical implications in the automation of the aortic root and ascending aorta assessment to improve workflow efficiency.

Genotype-Phenotype Correlation in Familial BAG3 Mutation Dilated Cardiomyopathy.

We report the case of a 22-year-old male who visited a cardiologist after the first episode of atrial fibrillation (AF). Echocardiography and magnetic resonance imaging revealed decreased left ventricular (LV) systolic function with dilated LV. An intermittent second-degree AV (atrioventricular) block was detected during 24 h Holter monitoring. Genetic test revealed the pathogenic variant of the BAG3 (BLC2-associated athanogene 3) gene. Due to the high risk of heart failure (HF) progression and ventricular arrhythmias, an event recorder was implanted and a pathogenetic HF treatment was prescribed. The analysis of genealogy revealed that the patient's father, at the age of 32, was diagnosed with dilated cardiomyopathy (DCM) and recurrent AF episodes. Genetic testing also confirmed a pathogenic variant of the BAG3 gene. Currently, with the optimal treatment of HF, the patient's disease has been stable for three years and the condition is closely monitored on an outpatient basis. So, we demonstrate the importance of early detection for genetic testing and the unusual stability exhibited by the patient's optimal medical therapy for 3 years.

Neuroanatomy of the Pig Cardiac Ventricles. A Stereomicroscopic, Confocal and Electron Microscope Study.

Although the pig is a model for heart disease, the neuroanatomy of cardiac ventricles (CV) in this species remains undetailed. We aimed to define the innervation pattern of pig CV, combining histochemistry for acetylcholinesterase, immunofluorescent labeling and electron microscopy. Forty nine examined pig hearts show that the major nerves supplying the ventral side of CV descend from the venous part of the heart hilum. Fewer in number and smaller in size, epicardial nerves supply the dorsal half of the CV. Epicardial nerves on the left ventricle are thicker than those on the right. Ventricular ganglia of various sizes distribute at the basal level of both CV. Averagely, we found 3,848 ventricular neuronal somata per heart. The majority of somata were cholinergic, although ganglionic cells of different neurochemical phenotypes (positive for nNOS, ChAT/nNOS, or ChAT/TH) were also observed. Large and most numerous nerves proceeded within the epicardium. Most of endocardium and myocardium contained a network of nerve bundles and nerve fibers (NFs). But, a large number of thin nerves extended along the bundle of His and its branches. The majority of NFs were adrenergic, while cholinergic NFs were scarce yet more abundant than nitrergic ones. Sensory NFs positive for CGRP were the second most abundant phenotype after adrenergic NFs in all layers of the ventricular wall. Electron microscopy elucidated that ultrastructure of nerves varied between different areas of CV. The described structural organization of CV provides an anatomical basis for further functional and pathophysiological studies in the pig heart. Anat Rec, 2017. © 2017 Wiley Periodicals, Inc. Anat Rec, 300:1756-1780, 2017. © 2017 Wiley Periodicals, Inc.

Innervation of the rabbit cardiac ventricles.

The rabbit is widely used in experimental cardiac physiology, but the neuroanatomy of the rabbit heart remains insufficiently examined. This study aimed to ascertain the architecture of the intrinsic nerve plexus in the walls and septum of rabbit cardiac ventricles. In 51 rabbit hearts, a combined approach involving: (i) histochemical acetylcholinesterase staining of intrinsic neural structures in total cardiac ventricles; (ii) immunofluorescent labelling of intrinsic nerves, nerve fibres (NFs) and neuronal somata (NS); and (iii) transmission electron microscopy of intrinsic ventricular nerves and NFs was used. Mediastinal nerves access the ventral and lateral surfaces of both ventricles at a restricted site between the root of the ascending aorta and the pulmonary trunk. The dorsal surface of both ventricles is supplied by several epicardial nerves extending from the left dorsal ganglionated nerve subplexus on the dorsal left atrium. Ventral accessing nerves are thicker and more numerous than dorsal nerves. Intrinsic ventricular NS are rare on the conus arteriosus and the root of the pulmonary trunk. The number of ventricular NS ranged from 11 to 220 per heart. Four chemical phenotypes of NS within ventricular ganglia were identified, i.e. ganglionic cells positive for choline acetyltransferase (ChAT), neuronal nitric oxide synthase (nNOS), and biphenotypic, i.e. positive for both ChAT/nNOS and for ChAT/tyrosine hydroxylase. Clusters of small intensely fluorescent cells are distributed within or close to ganglia on the root of the pulmonary trunk, but not on the conus arteriosus. The largest and most numerous intrinsic nerves proceed within the epicardium. Scarce nerves were found near myocardial blood vessels, but the myocardium contained only a scarce meshwork of NFs. In the endocardium, large numbers of thin nerves and NFs proceed along the bundle of His and both its branches up to the apex of the ventricles. The endocardial meshwork of fine NFs was approximately eight times denser than the myocardial meshwork. Adrenergic NFs predominate considerably in all layers of the ventricular walls and septum, whereas NFs of other neurochemical phenotypes were in the minority and their amount differed between the epicardium, myocardium and endocardium. The densities of NFs positive for nNOS and ChAT were similar in the epicardium and endocardium, but NFs positive for nNOS in the myocardium were eight times more abundant than NFs positive for ChAT. Potentially sensory NFs positive for both calcitonin gene-related peptide and substance P were sparse in the myocardial layer, but numerous in epicardial nerves and particularly abundant within the endocardium. Electron microscopic observations demonstrate that intrinsic ventricular nerves have a distinctive morphology, which may be attributed to remodelling of the peripheral nerves after their access into the ventricular wall. In conclusion, the rabbit ventricles display complex structural organization of intrinsic ventricular nerves, NFs and ganglionic cells. The results provide a basic anatomical background for further functional analysis of the intrinsic nervous system in the cardiac ventricles.

Subthreshold High-Frequency Electrical Field Stimulation Induces VEGF Expression in Cardiomyocytes.

Subthreshold electrical stimulation (SES) has been shown to induce an improvement of angiogenesis in ischemic and nonischemic skeletal muscles, mediated by increased VEGF expression. VEGF plays a key role in physiological and pathological angiogenesis. Cardiomyocytes possess the ability to synthesize and secrete VEGF. Thus, we thought to investigate the effect of SES on VEGF regulation in cultured neonatal rat ventricular myocytes (NRVMs), in the aim to reveal new techniques for therapeutic angiogenesis in ischemic heart disease. Cell cultures of NRVMs were electrically stimulated with field strengths below the myocyte depolarization threshold (0.5 V/cm with 1 ms bipolar impulse duration). Frequencies ranging from 5 Hz up to 25, 50, and 99 Hz were applied over a period of 48 h. The expression of VEGF and its receptor KDR was determined with Western blot and ELISA. To reveal the biological activity of the secreted VEGF amount, cultured human coronary artery endothelial cells (HCAECs) were treated with the cell culture supernatant of NRVMs exposed to SES. A dominant effect of SES was observed at 25 Hz. Within this particular frequency the VEGF protein amount in the cytoplasm as well as in the cell culture supernatant increased significantly. In parallel, the protein expression of the KDR receptor decreased in a significant manner. Moreover, cell culture supernatant of NRVMs exposed to SES augmented the growth of HCAECs. Cardiomyocytes respond to SES with an increase in biologically active VEGF expression that promotes cell proliferation of HCAECs. This mechanism may provide new approaches to develop therapeutic angiogenesis in the ischemic heart.

Radiofrequency catheter ablation of pulmonary vein roots results in axonal degeneration of distal epicardial nerves.

BACKGROUND: In treatment of atrial fibrillations (AF), radiofrequency ablation (RFA) at the pulmonary vein (PV) roots isolates AF triggers in the myocardial sleeves, but also can destroy PV ganglia and branches of the intrinsic cardiac nerve plexus. AIM: To determine the long-term impact of RFA at the PV roots on the structure of epicardial nerves located distally from the RFA site. METHODS: Five black-faced sheep underwent epicardial RFA of the left and middle PV roots. Two to 3 months after RFA, we obtained samples of epicardial nerves from remote locations of the left dorsal (LD) neural subplexus that extends along the roots of the superior PVs toward the coronary sinus (CS) and dorsal left ventricle (LV). Right atrial epicardial nerves from the right ventral (RV) neural subplexus of the ablated animals and epicardial nerves from LD neural subplexus of five additional intact sheep were used as control. Nerve morphology was examined using histochemical, immunohistochemical and transmission electron microscopy. RESULTS: Histochemical acetylcholinesterase staining did not reveal any epicardial nerve alterations. However, tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT) staining showed clearly the reduced numbers of TH and ChAT immunoreactive (IR) nerve fibers within epicardial nerves derived from the remote LD subplexus; control samples from all examined animals were full of evenly distributed TH-IR and ChAT-IR nerve fibers. In sharp contrast to control nerves, numerous swollen or disintegrated axons and Schwann cells with pyknotic nuclei inside unmyelinated and myelinated nerve fibers were identified by electron microscopy of ultrathin sections of epicardial nerves from the CS and LV regions in all ablated animals. CONCLUSIONS: Degeneration of remote atrial and ventricular epicardial nerves is evident 2-3 months after epicardial RFA at the PV roots. Such nerves are likely to be non-functional. Therefore, long-term autonomic dysfunction is a potential risk of PV isolation by RFA.

Association of echocardiographic atrial size and atrial fibrosis in a sequential model of congestive heart failure and atrial fibrillation.

BACKGROUND: Cardioversion (CV) success of atrial fibrillation (AF) inversely correlates to the size of the left atrium (LA). Atrial fibrillation and its most important risk factor, congestive heart failure (CHF), both induce atrial structural enlargement and fibrosis. To investigate the effect of AF and CHF on atrial dilatation and fibrosis, and to estimate whether echocardiographically determined atrial size may be used as a marker for atrial fibrosis. METHODS: In six dogs, pacemakers were implanted followed by HIS bundle ablation. After 4 weeks of rapid ventricular stimulation (185 bpm) for CHF induction, additional rapid atrial stimulation (500 bpm) was maintained for 7 weeks to induce AF. Serial determinations of echocardiographic atrial size were performed. Seven dogs with sinus rhythm served as histological controls. Postmortem tissue was obtained to determine the degree and composition of atrial fibrosis. RESULTS: While the ejection fraction of the AF/CHF dogs decreased significantly from 57+/-5% to 19+/-7% (P<.01), an increased degree of atrial fibrosis was found (right atrium [RA], 4.9+/-2.0% to 19.9+/-5.4%; LA, 4.4+/-1.6% to 22.2+/-3.2%; P<.01), accompanied by a significant increase of atrial volumes (LA: 21+/-4 to 44+/-4 mm3; P<.01; RA: 10+/-3 to 18+/-6 mm3; P<.05) and LA diameters (34+/-4 to 43+/-2 mm, P<.05). Atrial fibrosis and size significantly correlated. CONCLUSIONS: Atrial fibrillation/CHF leads to a significant atrial fibrosis and dilation. The increased echocardiographic size correlates to the degree of atrial fibrosis and may be used as clinical marker for atrial fibrosis. The fibrosis accompanying atrial dilatation may also explain why LA size, as determined by echocardiography, is a strong predictor of CV success.

Decreased plasminogen activator inhibitor and tissue metalloproteinase inhibitor expression may promote increased metalloproteinase activity with increasing duration of human atrial fibrillation.

INTRODUCTION: Atrial fibrosis has been shown to concur with the persistence of atrial fibrillation (AF) and is only incompletely reversible, thus counteracting attempts to restore and maintain sinus rhythm (SR). Besides the angiotensin system, the matrix metalloproteinases (MMP) play a major role in the pathogenesis of fibrosis. Thus, the present study investigated changes of the MMP system during the development of human AF. METHODS AND RESULTS: Right atrial appendages of 146 patients were excised during heart surgery and grouped according to rhythm (SR vs AF) and AF duration. Hydroxyproline as a surrogate for collagen content and morphometrically determined collagen content increased significantly from SR (14.3 +/- 7.7%) to chronic permanent AF (CAF) of 6-24 months (21.2 +/- 9.2%, P = 0.02), and CAF of > 60 months (25.3 +/- 4.7%, P < 0.01). From SR to paroxysmal and chronic persistent AF (CPAF) and to CAF MMP-2 and MMP-9 activity rose, while their mRNA and protein levels were not altered significantly. Plasminogen activator inhibitor (PAI), an inhibitor of a potent activator of many MMPs, was significantly decreased with increasing duration of AF. In parallel, the mRNA levels of the tissue inhibitors of MMPs TIMP-1 and -2 decreased significantly. CONCLUSION: Human atrial fibrogenesis is enhanced with increasing duration of AF: a longer AF duration is associated with elevated atrial interstitial MMP activity, but decreased PAI and TIMP expression.

Simultaneous transesophageal cardioversion and echocardiography: feasibility and safety.

BACKGROUND: Transesophageal echocardiography (TEE) is routinely used to exclude atrial thrombus prior to cardioversion of atrial fibrillation (AF). Because the TEE probe lies adjacent to the atria, cardioversion using an electrode attached to the TEE probe should allow for immediate low-energy transesophageal cardioversion. OBJECTIVE: The purpose of this study was to evaluate a cardioversion electrode sheath that can be affixed to conventional TEE probes for simultaneous thrombus exclusion and cardioversion of AF. METHODS: A thin electrode was integrated into a latex or polyurethane sheath covering a conventional TEE probe. TEE thrombus exclusion and biphasic transesophageal cardioversion using a step-up protocol were performed during deep sedation. Esophagoscopy was performed immediately after cardioversion and after 1 week. RESULTS: TEE was performed in 27 patients. One patient showed left atrial thrombi. Transesophageal cardioversion was successful in 25 of the remaining 26 patients. Mean atrial cardioversion threshold was 63 +/- 48 J. Transesophageal cardioversion restored sinus rhythm in two patients with unsuccessful transthoracic cardioversion. Transesophageal cardioversion in deep sedation was well tolerated. Esophagoscopy revealed slight mucosal damage in three patients at the site of shock application; two of these patients showed signs of gastroesophageal reflux disease. Mucosal damage unrelated to the site of shock delivery was noted in three patients. CONCLUSION: Atrial thrombus exclusion and transesophageal cardioversion of AF via a disposable cardioversion sheath offers the opportunity to perform transesophageal cardioversion and TEE thrombus exclusion during one sedation. It may not be suitable for use in patients with gastroesophageal reflux disease. Transesophageal cardioversion may establish sinus rhythm in selected patients refractory to transthoracic cardioversion.