All-Cause Mortality of Atrial Fibrillation and Heart Failure in the Same Patient: Does the Order Matter?

INTRODUCTION: Atrial fibrillation (AF) and heart failure (HF) often coexist due to the common elements of the pathomechanism they share. The potential significance of the order these entities present in the same patient is ill-defined. Herein, we report our results from a nationwide database on the occurrence of various sequences AF and HF may present, the time delays between the two conditions and all-cause mortality associated with different scenarios. METHODS: Patients diagnosed with both AF and HF between 2015 and 2021 were enrolled from the Hungarian National Health Insurance Fund (NHIF) database. The order the two entities followed each other, and the time delay in between were registered. Median survival rates were calculated in AF → HF; HF → AF and simultaneous scenarios. RESULTS: A total of 109,075 patients were enrolled: 29,937 with AF → HF, 38,171 with HF → AF, and 40,967 diagnosed simultaneously. Time delays between AF → HF and HF → AF were 6 and 10 months, respectively. The median survival was 46 months in the AF → HF, 38 months in the HF → AF, and 21 months in the simultaneous group. Patients with HF → AF, and with simultaneous presentations had 5% and 16% greater mortality risk as compared to the AF → HF sequence, with hazard ratios (95% confidence intervals) of 0.95 (0.93-0.97) and 0.84 (0.82-0.85), respectively (P < 0.0001). CONCLUSIONS: HF occurred significantly earlier after the diagnosis of AF than vice versa. Patients diagnosed simultaneously had the worst, while the AF → HF sequence had the best prognosis. These data should have implications for the intensification of monitoring and therapy in different scenarios.

Electrophysiology lab efficiency using cryoballoon for pulmonary vein isolation in central and eastern Europe: A sub-analysis of the cryo global registry study.

BACKGROUND: Cryoballoon ablation for treatment of atrial fibrillation (AF) reduces procedure times, but limited data is available about its impact on electrophysiology (EP) lab efficiency in Central and Eastern Europe (CEE). Using CEE-specific procedure data, the present study modeled cryoballoon ablation procedures on EP lab resource consumption to improve efficiency. METHODS: A discrete event simulation model was developed to assess EP efficiency with cryoballoon ablation. Model inputs were taken from CEE sites within the Cryo Global Registry, namely Czech Republic, Hungary, Poland, Serbia, and Slovakia. The main endpoints were percentage of days that resulted in overtime and percentage of days with time for one extra simple EP procedure. Use of the 'figure of 8' (Fo8) closure technique to reduce procedure time was also examined. RESULTS: The mean lab occupancy time across all CEE sites was 133 ± 47 minutes (min: 104 minutes, max:181 minutes). Cryoballoon ablation in the base-case scenario resulted in 14.6% of days with overtime and 64.8% of days with time for an extra simple EP procedure. Use of the Fo8 closure technique enhanced these values to 5.5% and 85.3%, respectively. Model endpoints were most sensitive to changes in lab occupancy times and overtime start time. CONCLUSIONS: In this CEE-specific analysis of EP lab efficiency it was found that 3 cryoballoon ablation procedures could be performed in 1 lab day, leaving time for a 4th simple EP procedure on most days. As such, use cryoballoon ablation for PVI is an effective way to improve EP lab efficiency.

Add-on Sacubitril/Valsartan Therapy Induces Left Ventricular Remodeling in Non-responders to Cardiac Resynchronization Therapy to a Similar Extent as in Heart Failure Patients Without Resynchronization.

INTRODUCTION: Non-responders to cardiac resynchronization therapy (CRT-NR) have poor prognosis. Sacubitril/valsartan (SV) treatment improved the outcome of patients with heart failure with reduced left ventricular (LV) ejection fraction (HFrEF) in randomized trials with no data on the specific cohort of CRT-NRs. The aim of this study was to compare the echocardiographic and biomarker changes in CRT-NR patients treated with versus without SV, and in patients with HFrEF on SV therapy. METHODS: CRT-NR patients initiated on SV (group I), CRT-NR patients on angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARB) (group II), and patients with HFrEF (without CRT) initiated on SV (group III) were identified in our heart failure (HF) registry. CRT-NR was defined as < 10% improvement in left ventricular ejection fraction (LV EF) 6 months after the implantation. Echocardiographic parameters and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels at baseline and at the end of follow-up were compared. RESULTS: A total of 275 patients (group I, 70; group II, 70; and group III, 135) were included. After a follow-up of 7.54 ± 1.8 months (mean ± standard deviation [SD]), LV EF (%) increased in group I (25.2 ± 5.7 versus 29.4% ± 6.7; p < 0.001) and in group III (26.6 ± 6.4 versus 29.9 ± 6.7; p < 0.001). LV end-systolic diameters (mm) decreased in group I (56.6 ± 9.0 versus 54.3 ± 8.7; p = 0.004) and in group III (55.9 ± 9.9 versus 54.3 ± 11.2; p = 0.021). The levels of NT-proBNP (pg/mL) decreased in group I (2058.86 [1041.07-4502.51] versus 1121.55 [545-2541]; p < 0.001) and in group III (2223.35 [1233.03-4795.96] versus 1123.09 [500.38-2651.27]; p < 0.001). The extent of improvement was similar in groups I and III (p > 0.05). No significant changes were detected in group II. CONCLUSION: SV therapy induced similar improvements in echocardiographic parameters and in NT-proBNP levels in CRT-NR patients and in patients with HFrEF without resynchronization.

Technically Challenging Percutaneous Interventions of Chronic Total Occlusions Are Associated with Enhanced Platelet Activation.

Percutaneous coronary intervention (PCI) is a frequently performed treatment option for recanalization in patients with chronic total occlusion (CTO). As CTO-PCIs are often complicated and challenging for interventionalists, the stressful and damaging nature of the procedure can be remarkable, thus platelets can be easily activated. Our aim was to investigate the effect of CTO-PCI on platelet activation and the expression of selected circulating microRNAs (miR) of platelet and endothelium origin after CTO-PCI. In this study, 50 subjects after CTO-PCI were enrolled. Blood samples were obtained before PCI, at 2 days and 3-6 months after the procedure to measure the degree of platelet activation and the level of plasma miR-223, miR-181b, and miR-126. Patients were divided based on the characteristics of the intervention. Patients with higher Japanese CTO scores and longer duration of PCI showed significantly elevated platelet P-selectin positivity (p = 0.004 and p = 0.013, respectively) 2 days after the procedure compared to pre-PCI and increased concentration of soluble P-selectin 3-6 months after the intervention (higher Japanese CTO score: p = 0.028 and longer duration of PCI: p = 0.023) compared to baseline values. Shorter total stent length caused a significantly lower miR-181b expression at 3-6 months after the intervention (p = 0.031), while no difference was observed in miR-223 and miR-126. One stent thrombosis occurred during the follow-up period. Although these technically challenging CTO-PCIs may cause enhanced platelet activation right after the intervention and long-term endothelial cell dysfunction, these interventions are not associated with more adverse clinical events.

Right superior pulmonary vein parameter determined by three-dimensional transesophageal echocardiography is an independent predictor of the outcome after cryoballoon isolation of the pulmonary veins.

BACKGROUND: A direct comparison of three-dimensional transesophageal echocardiography (3DTEE) and cardiac computed tomography imaging has demonstrated good inter-technique agreement for the following pulmonary vein (PV) parameters: the ostium area of the right superior PV (RSPV) and its major (a) and minor axis (b) diameters, the left lateral ridge and the minor axis (b) diameter of the left superior PV. Herein, under investigation, was the predictive value of these parameters for arrhythmia recurrence (AR) after PV isolation with the 28 mm second generation cryoballoon (CBG2). METHODS: One hundred eleven patients (67 men, mean age 58.06 ± 10.58 years) undergoing 3DTEE before PV isolation with the CBG2 for paroxysmal atrial fibrillation were followed. "Point by point" redo intervention was offered in case of AR and reconnected PVs were defined. RESULTS: During a mean follow-up of 617 ± 258.86 days, 65 (58.9%) patients remained free of AR. Longer RSPV b was found to be the only significant predictor for AR (hazard ratio [HR] 1.059; 95% confidence interval [CI] 1.000-1.121; p = 0.048). RSPV b ≥ 28 mm resulted in a threefold (HR 3.010; 95% CI 1.270-7.134, p = 0.012) increase in the risk of AR. The association of RSPV b with AR was independent of the biophysical parameters of cryoapplications. In 25 "redo" patients, reconnections were found 1.75 times more likely in the RSPV than in the other 3 PVs altogether. CONCLUSIONS: Right superior PV b measured with 3DTEE might be a significant predictor of AR after PV isolation with the CBG2. In case of RSPV b exceeding 28 mm, alternative PV isolation techniques or use of a larger balloon might be considered.

Decreased level of serum NT-proCNP associates with disease severity in COVID-19.

BACKGROUND: C-type natriuretic peptide (CNP) is an endothelium-derived paracrine molecule with an important role in vascular homeostasis. In septic patients, the serum level of the amino-terminal propeptide of CNP (NT-proCNP) shows a strong positive correlation with inflammatory biomarkers and, if elevated, correlates with disease severity and indicates a poor outcome. It is not yet known whether NT-proCNP also correlates with the clinical outcome of patients suffering from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the current study, we aimed to determine possible changes in the NT-proCNP levels of patients with coronavirus disease 2019 (COVID-19), with special regard to disease severity and outcome. METHODS: In this retrospective analysis, we determined the serum level of NT-proCNP in hospitalized patients with symptoms of upper respiratory tract infection, using their blood samples taken on admission, stored in a biobank. The NT-proCNP levels of 32 SARS-CoV-2 positive and 35 SARS-CoV-2 negative patients were measured to investigate possible correlation with disease outcome. SARS-CoV-2 positive patients were then divided into two groups based on their need for intensive care unit treatment (severe and mild COVID-19). RESULTS: The NT-proCNP was significantly different in the study groups (e.g. severe and mild COVID-19 and non-COVID-19 patients), but showed inverse changes compared to previous observations in septic patients: lowest levels were detected in critically ill COVID-19 patients, while highest levels in the non-COVID-19 group. A low level of NT-proCNP on admission was significantly associated with severe disease outcome. CONCLUSIONS: Low-level NT-proCNP on hospital admission is associated with a severe COVID-19 disease course. The pathomechanism underlying this observation remains to be elucidated, while future studies in larger patient cohorts are necessary to confirm these observations and reveal therapeutic importance. Trial registration DRKS00026655 Registered 26. November 2021.

Atrial Fibrillation Related Coronary Embolism: Diagnosis in the Focus.

Atrial fibrillation (AF) is the most common arrhythmia in myocardial infarction (MI). AF can be caused by ischemia, and MI can be caused by AF. Additionally, 4-5% of MI cases are related to coronary embolism (CE), and one-third of cases are attributed to AF. Our aim was to investigate the prevalence of AF-related CE cases among 3 consecutive years of STEMI cases. We also aimed to reveal the diagnostic accuracy of the Shibata criteria scoring system and the role of thrombus aspiration. Among 1181 STEMI patients, 157 had AF (13.2%). By using the Shibata's diagnostic criteria, 10 cases were classified as 'definitive' and 31 as 'probable' CE. After re-evaluation, a further five cases were classified as 'definitive'. Further analysis of the 15 CE cases revealed that CE was more prevalent in patients with previously known (n = 10) compared to those with new-onset (n = 5) AF (16.7% vs. 5.1%, p = 0.024). A PubMed search was performed, and 40 AF-related cases were found where the Shibata's criteria could be applied. Further, 31 cases could be classified as 'definitive', 4 as 'probable' and, in 5 cases, the embolic origin could be excluded. In 40% of reported cases and in 47% of our cases, thrombus aspiration helped in diagnosis.

Three-dimensional transesophageal echocardiographic evaluation of pulmonary vein anatomy prior to cryoablation: validation with cardiac CT scan.

BACKGROUND: Anatomical characteristics of the left atrium and the pulmonary veins (PVs) may be relevant to the success rate of cryoballoon (CB)-ablation for atrial fibrillation (AF). Cardiac computed tomography (CCT) is considered as the gold standard for preablation imaging. Recently, three-dimensional transesophageal echocardiography (3DTOE) has been proposed for preprocedural assessment of cardiac structures relevant to CB-ablation. The accuracy of 3DTOE has not been validated by other imaging modalities. OBJECTIVE: We prospectively evaluated the feasibility and the accuracy of 3DTOE imaging for the assessment of left atrial and PV structures prior to pulmonary vein isolation (PVI). In addition, CCT was used to validate the measurements obtained with 3DTOE. METHODS: PV anatomy of 67 patients (59.7% men, mean age 58.5 ± 10.5 years) was assessed using both 3DTOE and CCT scan prior to PVI with the Arctic Front CB. The following parameters were measured bilaterally: PV ostium area (OA), the major and minor axis diameters of the ostium (a > b) and the width of the carina between the superior and the inferior PVs. In addition, the width of the left lateral ridge (LLR) between the left atrial appendage and the left superior PV. Evaluation of inter-technique agreement was based on linear regression with Pearson correlation coefficient (PCC) and Bland-Altman analysis of biases and limits of agreement. RESULTS: Moderate positive correlation (PCC 0.5-0.7) was demonstrated between the two imaging methods for the right superior PV's OA and both axis diameters, the width of the LLR and left superior PV (LSPV) minor axis diameter (b) with limits of agreement ˂50% and no significant biases. Low positive or negligible correlation (PCC < 0.5) was found for both inferior PV parameters. CONCLUSIONS: Detailed assessment of the right superior PV parameters, LLR and LSPV b is feasible with 3DTOE prior to AF ablation. This 3DTOE measurements demonstrated a clinically acceptable inter-technique agreement with those obtained with CCT.

Mortality on DOACs Versus on Vitamin K Antagonists in Atrial Fibrillation: Analysis of the Hungarian Health Insurance Fund Database.

PURPOSE: Limited real-world data are available on the survival of patients treated with vitamin K antagonists (VKAs) versus with direct oral anticoagulants (DOACs) for nonvalvular atrial fibrillation (AF). In this nationwide registry, we analyzed the mortality risk of patients with nonvalvular AF taking DOACs versus VKAs, with a special attention to the early treatment period. METHODS: The Hungarian National Health Insurance Fund (NHIF) database was searched to identify patients treated with VKA or DOAC as a thromboembolic prophylaxis for nonvalvular AF between 2011 and 2016. The overall and the early (0-3, 4-6, and 7-12 months) mortality risks with the 2 types of anticoagulation were compared. A total of 144,394 patients with AF treated with either a VKA (n = 129,925) or a DOAC (n = 14,469) were enrolled. FINDINGS: A 28% improvement in 3-year survival with DOAC treatment compared with VKA treatment was shown. Mortality reduction with DOACs was consistent across different subgroups. However, younger patients (30-59 years old) initiated on DOAC therapy had the greatest RRR (53%) in mortality. Furthermore, DOAC treatment also yielded a benefit of greater magnitude (HR = 0.55; 95% CI, 0.40-0.77, P = 0.001) in the lower (0-1) CHA2DS2-VASc score segment and in those with fewer (0-1) bleeding risk factors (HR = 0.50, CI 0.34-0.73, P = 0.001). The RRR in mortality with DOACs was 33% within the first 3 months, and 6% in the second year. IMPLICATIONS: Thromboembolic prophylaxis with DOACs in this study yielded significantly lower mortality compared with VKA treatment in patients with nonvalvular AF. The largest benefit was shown in the early period after treatment initiation, as well as in younger patients, those with a lower CHA2DS2-VASc score, and those with fewer bleeding risk factors.

Omecamtiv mecarbil augments cardiomyocyte contractile activity both at resting and systolic Ca2+ levels.

AIMS: Heart failure with reduced ejection fraction (HFrEF) is a disease with high mortality and morbidity. Recent positive inotropic drug developments focused on cardiac myofilaments, that is, direct activators of the myosin molecule and Ca2+ sensitizers for patients with advanced HFrEF. Omecamtiv mecarbil (OM) is the first direct myosin activator with promising results in clinical studies. Here, we aimed to elucidate the cellular mechanisms of the positive inotropic effect of OM in a comparative in vitro investigation where Ca2+ -sensitizing positive inotropic agents with distinct mechanisms of action [EMD 53998 (EMD), which also docks on the myosin molecule, and levosimendan (Levo), which binds to troponin C] were included. METHODS: Enzymatically isolated canine cardiomyocytes with intact cell membranes were loaded with Fura-2AM, a Ca2+ -sensitive, ratiometric, fluorescent dye. Changes in sarcomere length (SL) and intracellular Ca2+ concentration were recorded in parallel at room temperature, whereas cardiomyocyte contractions were evoked by field stimulation at 0.1 Hz in the presence of different OM, EMD, or Levo concentrations. RESULTS: SL was reduced by about 23% or 9% in the presence of 1 µM OM or 1 µM EMD in the absence of electrical stimulation, whereas 1 µM Levo had no effect on resting SL. Fractional sarcomere shortening was increased by 1 µM EMD or 1 µM Levo to about 152%, but only to about 128% in the presence of 0.03 µM OM. At higher OM concentrations, no significant increase in fractional sarcomere shortening could be recorded. Contraction durations largely increased, whereas the kinetics of contractions and relaxations decreased with increasing OM concentrations. One-micromole EMD or 1 µM Levo had no effects on contraction durations. One-micromole Levo, but not 1 µM EMD, accelerated the kinetics of cardiomyocyte contractions and relaxations. Ca2+ transient amplitudes were unaffected by all treatments. CONCLUSIONS: Our data revealed major distinctions between the cellular effects of myofilament targeted agents (OM, EMD, or Levo) depending on their target proteins and binding sites, although they were compatible with the involvement of Ca2+ -sensitizing mechanisms for all three drugs. Significant part of the cardiotonic effect of OM relates to the prolongation of systolic contraction in combination with its Ca2+ -sensitizing effect.

Long-Term Changes in the Biomarkers of Left Atrial Fibrosis after Pulmonary Vein Isolation for Paroxysmal and Persistent Atrial Fibrillation.

Background: Atrial fibrillation (AF) is accompanied by inflammation and fibrosis to variable extent. The biomarkers of fibrosis were measured in patients with different forms of AF and cardiac status. Herein, we assessed the associations of the baseline concentrations of different biomarkers with the long-term success of pulmonary vein isolation (PVI) in patients with a structurally normal heart. Furthermore, we compared biomarker levels before and 3 years after ablation to gain further insights into the AF mechanism. Methods: Patients, undergoing PVI for paroxysmal/persistent AF were enrolled prospectively. Blood samples were obtained 24 hours before and 3 years after ablation. Serum cancer antigen 125 (CA-125), plasma Caspase-3, Galectin-3 and Cathepsin L concentrations were measured. Follow-up visits every 6 months included 12-lead electrocardiogram, 24-hour Holter, trans-telephonic monitoring as well as transthoracic echocardiography after ablation. Biomarker levels, left ventricular ejection fraction and left atrial (LA) diameters at baseline and at the 3-year follow-up were compared in patients with versus without AF recurrence. Results: A total of 63 patients were enrolled (23 women; age 61.4 ( ± 8.8) years). The acute isolation of all pulmonary veins was achieved in all patients. During a mean follow-up of 36.3 ± 6.3 months, AF recurrence was demonstrated in 26 (41.3%) patients. No significant differences were demonstrated in the levels of CA-125, Galectin-3, Caspase-3 and Cathepsin L pre- and post-ablation in patients with versus without AF recurrence. A significant decrease was detected in the concentrations of Caspase-3, Galectin-3 and Cathepsin L during follow-up with no difference in patients with versus without AF recurrence. A positive correlation was found between Caspase-3 levels and LA diameters in the AF recurrence group both before (r = 0.477; p = 0.018) and after the procedure (r = 0.533; p = 0.019). Conclusions: Our results demonstrated that the levels of CA-125, Caspase-3, Cathepsin L and Galectin-3 are not associated with AF recurrence after PVI in patients with a structurally normal heart and mainly paroxysmal AF. Except for CA-125, all the other biomarkers demonstrated a significant decrease during a 3-year follow-up post-ablation. Furthermore, Caspase-3 levels demonstrated a positive correlation with LA dimensions in patients with AF recurrence.

Subclinical systolic and diastolic myocardial dysfunction in polyphasic polymyositis/dermatomyositis: a 2-year longitudinal study.

BACKGROUND: Cardiac involvement in patients with idiopathic inflammatory myopathies (IIM) is associated with increased morbidity and mortality risk; however, little is known about the progression of cardiac dysfunction and long-term data are scarce. In the present work, we intended to prospectively study echocardiographic parameters in patients with IIM for 2 years. METHODS: Twenty-eight IIM patients (41.9±1.6 years) without cardiovascular symptoms were enrolled. Patients with monophasic/polyphasic disease patterns were studied separately and compared to age-matched healthy individuals. Conventional echocardiographic and tissue Doppler imaging (TDI) parameters of systolic [LV: ejection fraction (EF), mitral annulus systolic movement (MAPSE), lateral s') and diastolic left (mitral inflow velocities, lateral anulus velocities: e', a', E/e') and right ventricular function (fractional area change: FAC, tricuspid annulus plane systolic excursion: TAPSE) were measured at the time of the diagnosis and 2 years later. RESULTS: Subclinical LV systolic dysfunction is characterized by reduced lateral s' (10.4 vs. 6.4 cm/s, p<0.05), EF (62.6±0.6%, vs. 51.7±0.7%) and MAPSE (18.5±0.6 vs. 14.5±0.6 mm) could be observed in IIM patients with polyphasic disease course 2 years after diagnosis compared to controls. Furthermore, diastolic LV function showed a marked deterioration to grade I diastolic dysfunction at 2 years in the polyphasic group (lateral e': 12.9 ±0.6, vs. 7.4±0.3 cm/s; lateral a': 10.7±0.3, vs. 17.3±0.8 cm/s; p<0.05) supported by larger left atrium (32.1±0.6 vs. 37.8±0.6 mm; p<0.05]. TDI measurements confirmed subclinical RV systolic dysfunction in polyphasic patients 2 years after diagnosis (FAC: 45.6±1.8%, vs. 32.7±1.4%; TAPSE: 22.7±0.5, vs. 18.1±0.3 mm; p<0.05). Similar, but not significant tendencies could be detected in patients with monophasic disease patterns. Polyphasic patients showed significantly (p<0.05) worse results compared to monophasic patients regarding EF (51.7±0.7% vs. 58.1±0.6%), lateral s' (6.4±0.4 cm/sec vs. 8.6±0.4 cm/s,), left atrium (37.8±0.6 mm vs. 33.3±0.8 mm), FAC (32.7±1.4% vs. 41.0±1.6%) and TAPSE (18.1±0.3 mm vs. 21.3±0.7 mm). CONCLUSIONS: Significant subclinical cardiac dysfunction could be detected in IIM patients with polyphasic disease course 2 years after diagnosis, which identifies them as a high-risk population. TDI is a useful method to detect echocardiographic abnormalities in IIM complementing conventional echocardiography and can recognize the high cardiac risk.

Predictors of restenosis following percutaneous coronary stent implantation: The role of trimetazidine therapy.

Aims: In-stent restenosis (ISR) is an unresolved problem following percutaneous coronary intervention (PCI), having a negative impact on clinical outcome. The main goal of this study was to find new independent predictors that may influence the development of ISR. Methods and results: In this retrospective analysis, 653 PCI patients were involved. All patients had coronary stent implantation and a follow-up coronary angiography. Based on the presence of ISR at follow-up, patients were divided into two groups: 221 in the ISR and 432 in the control group. When evaluating the medical therapy of patients, significantly more patients were on trimetazidine (TMZ) in the control compared to the ISR group (p = 0.039). TMZ was found to be an independent predictor of a lower degree of ISR development (p = 0.007). TMZ treatment was especially effective in bare metal stent (BMS)-implanted chronic coronary syndrome (CCS) patients with narrow coronary arteries. The inflammation marker neutrophil to lymphocyte ratio (NLR) was significantly elevated at baseline in the ISR group compared to controls. The reduction of post-PCI NLR was associated with improved efficacy of TMZ to prevent ISR development. Drug eluting stent implantation (p < 0.001) and increased stent diameter (p < 0.001) were the most important independent predictors of a lower degree of ISR development, while the use of longer stents (p = 0.005) was a major independent predictor of an increased ISR risk. Conclusion: TMZ reduces the occurrence of ISR following PCI, with special effectiveness in BMS-implanted patients having CCS and narrow coronary arteries. TMZ treatment may help to lower ISR formation in countries with high BMS utilization rates.

Effect of invasive therapeutic coronary interventions on endothelial cell activation and thrombin generation in patients with chronic total coronary occlusion.

BACKGROUND: Percutaneous coronary intervention (PCI) is commonly used treatment for chronic total occlusion (CTO). PCI can be performed in two different ways using wire escalation (WE) or subintimal dissection and reentry (DR) technique. During both procedures patients are treated with anticoagulants, however a substantial activation of coagulation cascade is expected, which may affect clinical outcome. OBJECTIVES: Our aim was to compare the impact of WE and DR techniques regarding endothelial cell activation and thrombin formation. METHODS: Fifty patients after CTO-PCI were enrolled into this study. Blood samples were obtained before PCI, at 48 h and 3-6 months after the intervention to measure soluble endothelium-specific markers and to investigate thrombin generation. RESULTS: Twenty-nine patients were treated with WE, 21 received DR. In the DR group, soluble VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular cell adhesion molecule-1) concentrations were gradually elevated and remained significantly increased at 3-6 months (p = 0.006 and p = 0.037, respectively) compared to pre-PCI. Furthermore, significant decrease in lagtime (p = 0.004) and time to peak (p = 0.002) with a substantial increment in peak thrombin (p = 0.001) were observed in these patients. In contrast, no significant alteration was found in the WE cohort. Clinical complications (myocardial infarction, stroke, thrombosis, revascularization) did not occur in the first 9 months of follow-up period in either group. CONCLUSION: Although DR intervention induces more thrombin generation with a larger degree of endothelium activation compared to WE, this technique does not cause more clinical complications.

The feasibility of baroreflex sensitivity measurements in heart failure subjects: The role of slow-patterned breathing.

INTRODUCTION: Increased muscle sympathetic nerve activity (MSNA) indicates an adverse outcome in heart failure. Decreased baroreflex modulation of MSNA is a well-known feature of the disease. The determinability of cardiovagal baroreflex sensitivity (BRS) in heart failure is low, however, the determinability of sympathetic BRS is not known. METHODS: We have assessed the spontaneous, MSNA burst incidence-based baroreflex index (BRSsymp) in 33 stable heart failure patients and in 10 healthy controls using the traditional r ≥ .5 cutoff for acceptable individual diastolic pressure-burst incidence slopes, and also a more stringent r ≥ .7 cutoff. We have also assessed the influence of 6/min breathing. RESULTS: The determinability of BRSsymp in heart failure patients was 64% during spontaneous breathing with r ≥ .5 cutoff, and 39% using the r ≥ .7 cutoff. The determinability of these indices further decreased during 6/min breathing, dropping to 29% with the r ≥ .7 cutoff. In contrast, the determinability of the cardiovagal BRS indices increased significantly with 6/min breathing (from 24% to 66%; p < .001). Patients who still had determinable BRSsymp at the r ≥ .7 cutoff had a significantly lower baseline burst incidence than those with an undeterminable index (70 ± 14 vs. 89 ± 10 burst/100 cycles; p < .002). Neither the 6/min breathing, nor the r ≥ .7 cutoff limit influenced the high availability of BRSsymp in healthy subjects. CONCLUSION: The determinability of BRSsymp in heart failure patients is limited, especially with the 0.7 limit for correlation. Undeterminable BRSsymp in patients is associated with higher sympathetic activity. 6/min breathing improves the determinability of cardiovagal BRS indices, but not that of BRSsymp.

The Novel Cardiac Myosin Activator Danicamtiv Improves Cardiac Systolic Function at the Expense of Diastolic Dysfunction In Vitro and In Vivo: Implications for Clinical Applications.

Recent cardiotropic drug developments have focused on cardiac myofilaments. Danicamtiv, the second direct myosin activator, has achieved encouraging results in preclinical and clinical studies, thus implicating its potential applicability in the treatment of heart failure with reduced ejection fraction (HFrEF). Here, we analyzed the inotropic effects of danicamtiv in detail. To this end, changes in sarcomere length and intracellular Ca2+ levels were monitored in parallel, in enzymatically isolated canine cardiomyocytes, and detailed echocardiographic examinations were performed in anesthetized rats in the absence or presence of danicamtiv. The systolic and diastolic sarcomere lengths decreased; contraction and relaxation kinetics slowed down with increasing danicamtiv concentrations without changes in intracellular Ca2+ transients in vitro. Danicamtiv evoked remarkable increases in left ventricular ejection fraction and fractional shortening, also reflected by changes in systolic strain. Nevertheless, the systolic ejection time was significantly prolonged, the ratio of diastolic to systolic duration was reduced, and signs of diastolic dysfunction were also observed upon danicamtiv treatment in vivo. Taken together, danicamtiv improves cardiac systolic function, but it can also limit diastolic performance, especially at high drug concentrations.

Comparison of management and outcomes of ST-segment elevation myocardial infarction patients in Estonia, Hungary, Norway, and Sweden according to national ongoing registries.

AIMS: Describe the characteristics, management and outcomes of hospitalized ST-segment elevation myocardial infarction (STEMI) patients according to national ongoing myocardial infarction registries in Estonia, Hungary, Norway, and Sweden. METHODS AND RESULTS: Country-level aggregated data was used to study baseline characteristics, use of in-hospital procedures, medications at discharge, in-hospital complications, 30-day and 1-year mortality for all patients admitted with STEMI during 2014-2017 using data from EMIR (Estonia; n = 4584), HUMIR (Hungary; n = 23 685), NORMI (Norway; n = 12 414, data for 2013-2016), and SWEDEHEART (Sweden; n = 23 342). Estonia and Hungary had a higher proportion of women, patients with hypertension, diabetes, and peripheral artery disease compared to Norway and Sweden. Rates of reperfusion varied from 75.7% in Estonia to 84.0% in Sweden. Rates of recommendation of discharge medications were generally high and similar. However, Estonia demonstrated the lowest rates of dual antiplatelet therapy (78.1%) and statins (86.5%). Norway had the lowest rates of beta-blockers (80.5%) and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (61.5%). The 30-day mortality rates ranged between 9.9% and 13.4% remaining lowest in Sweden. One-year mortality rates ranged from 14.8% in Sweden and 16.0% in Norway to 20.6% in Hungary and 21.1% in Estonia. Age-adjusted lethality rates were highest for Hungary and lowest for Sweden. CONCLUSION: This inter-country comparison of data from four national ongoing European registries provides new insights into the risk factors, management and outcomes of patients with STEMI. There are several possible reasons for the findings, including coverage of the registries and variability of baseline-characteristics' definitions that need to be further explored.

Changes in the SARS-CoV-2 cellular receptor ACE2 levels in cardiovascular patients: a potential biomarker for the stratification of COVID-19 patients.

Angiotensin-converting enzyme 2 (ACE2) is essential for SARS-CoV-2 cellular entry. Here we studied the effects of common comorbidities in severe COVID-19 on ACE2 expression. ACE2 levels (by enzyme activity and ELISA measurements) were determined in human serum, heart and lung samples from patients with hypertension (n = 540), heart transplantation (289) and thoracic surgery (n = 49). Healthy individuals (n = 46) represented the controls. Serum ACE2 activity was increased in hypertensive subjects (132%) and substantially elevated in end-stage heart failure patients (689%) and showed a strong negative correlation with the left ventricular ejection fraction. Serum ACE2 activity was higher in male (147%), overweight (122%), obese (126%) and elderly (115%) hypertensive patients. Primary lung cancer resulted in higher circulating ACE2 activity, without affecting ACE2 levels in the surrounding lung tissue. Male sex resulted in elevated serum ACE2 activities in patients with heart transplantation or thoracic surgery (146% and 150%, respectively). Left ventricular (tissular) ACE2 activity was unaffected by sex and was lower in overweight (67%), obese (62%) and older (73%) patients with end-stage heart failure. There was no correlation between serum and tissular (left ventricular or lung) ACE2 activities. Neither serum nor tissue (left ventricle or lung) ACE2 levels were affected by RAS inhibitory medications. Abandoning of ACEi treatment (non-compliance) resulted in elevated blood pressure without effects on circulating ACE2 activities. ACE2 levels associate with the severity of cardiovascular diseases, suggestive for a role of ACE2 in the pathomechanisms of cardiovascular diseases and providing a potential explanation for the higher mortality of COVID-19 among cardiovascular patients. Abandoning RAS inhibitory medication worsens the cardiovascular status without affecting circulating or tissue ACE2 levels.

Sympathetic activation in heart failure with reduced and mildly reduced ejection fraction: the role of aetiology.

AIM: While sympathetic overactivity in heart failure (HF) with reduced ejection fraction (HFrEF; EF < 40%) is well-documented, it is ill-defined in patients with mildly reduced EF (HFmrEF; EF 40-49%). Furthermore, the significance of ischaemic versus non-ischaemic aetiology in sympathetic activation is also unclear and has yet to be studied in HF. Our goal was to compare muscle sympathetic nerve activity (MSNA) in HFmrEF and HFrEF patients and in healthy subjects, as well as to elucidate the influence of the underlying disease. METHODS AND RESULTS: Twenty-three HFrEF (age 58 ± 10 years), 33 HFmrEF patients (age 61 ± 10 years), including 11 subjects with non-ischaemic cardiomyopathy in each HF groups and 10 healthy controls (age 55 ± 10 years), were studied. MSNA-detected by peroneal microneurography, continuous arterial pressure, and ECG-was recorded. MSNA frequency (burst/min) and incidence (burst/100 cycles) were calculated. Association with the patients' characteristics were assessed, and aetiology-based comparisons were performed. Burst frequency demonstrated a significant stepwise increase in both HFmrEF (41 ± 11 burst/min) and HFrEF (58 ± 17 burst/min, P < 0.001) patients as compared with controls (27 ± 9; P < 0.001 for both HF groups). Similarly, burst incidences were 66 ± 17, 82 ± 15, and 36 ± 10 burst/100 cycles in HFmrEF, HFrEF patients, and in healthy controls, respectively (P < 0.001 for all). Burst frequencies in HF patients showed significant correlation with NT-proBNP levels, and significant inverse correlations with the subjects' mean RR intervals, stroke volumes, pulse pressures, and EF. CONCLUSIONS: Muscle sympathetic nerve activity parameters indicated significant sympathetic activation in both HFmrEF and HFrEF patients as compared with healthy controls with no difference in relation to ischaemic versus non-ischaemic aetiology.

Human Tissue Angiotensin Converting Enzyme (ACE) Activity Is Regulated by Genetic Polymorphisms, Posttranslational Modifications, Endogenous Inhibitors and Secretion in the Serum, Lungs and Heart.

Objective: Inhibitors of the angiotensin converting enzyme (ACE) are the primarily chosen drugs to treat heart failure and hypertension. Moreover, an imbalance in tissue ACE/ACE2 activity is implicated in COVID-19. In the present study, we tested the relationships between circulating and tissue (lung and heart) ACE levels in men. Methods: Serum, lung (n = 91) and heart (n = 72) tissue samples were collected from Caucasian patients undergoing lung surgery or heart transplantation. ACE I/D genotype, ACE concentration and ACE activity were determined from serum and tissue samples. Clinical parameters were also recorded. Results: A protocol for ACE extraction was developed for tissue ACE measurements. Extraction of tissue-localized ACE was optimal in a 0.3% Triton-X-100 containing buffer, resulting in 260 ± 12% higher ACE activity over detergent-free conditions. SDS or higher Triton-X-100 concentrations inhibited the ACE activity. Serum ACE concentration correlated with ACE I/D genotype (II: 166 ± 143 ng/mL, n = 19, ID: 198 ± 113 ng/mL, n = 44 and DD: 258 ± 109 ng/mL, n = 28, p < 0.05) as expected. In contrast, ACE expression levels in the lung tissue were approximately the same irrespective of the ACE I/D genotype (II: 1423 ± 1276 ng/mg, ID: 1040 ± 712 ng/mg and DD: 930 ± 1273 ng/mg, p > 0.05) in the same patients (values are in median ± IQR). Moreover, no correlations were found between circulating and lung tissue ACE concentrations and activities (Spearman's p > 0.05). In contrast, a significant correlation was identified between ACE activities in serum and heart tissues (Spearman's Rho = 0.32, p < 0.01). Finally, ACE activities in lung and the serum were endogenously inhibited to similar degrees (i.e., to 69 ± 1% and 53 ± 2%, respectively). Conclusion: Our data suggest that circulating ACE activity correlates with left ventricular ACE, but not with lung ACE in human. More specifically, ACE activity is tightly coordinated by genotype-dependent expression, endogenous inhibition and secretion mechanisms.