Sex-specific cardiovascular remodeling leads to a divergent sex-dependent development of heart failure in aged hypertensive rats.

INTRODUCTION: The prevalence of heart failure with preserved ejection fraction (HFpEF) is continuously rising and predominantly affects older women often hypertensive and/or obese or diabetic. Indeed, there is evidence on sex differences in the development of HF. Hence, we studied cardiovascular performance dependent on sex and age as well as pathomechanisms on a cellular and molecular level. METHODS: We studied 15-week- and 1-year-old female and male hypertensive transgenic rats carrying the mouse Ren-2 renin gene (TG) and compared them to wild-type (WT) controls at the same age. We tracked blood pressure and cardiac function via echocardiography. After sacrificing the 1-year survivors we studied vascular smooth muscle and endothelial function. Isolated single skinned cardiomyocytes were used to determine passive stiffness and Ca2+-dependent force. In addition, Western blots were applied to analyse the phosphorylation status of sarcomeric regulatory proteins, titin and of protein kinases AMPK, PKG, CaMKII as well as their expression. Protein kinase activity assays were used to measure activities of CaMKII, PKG and angiotensin-converting enzyme (ACE). RESULTS: TG male rats showed significantly higher mortality at 1 year than females or WT male rats. Left ventricular (LV) ejection fraction was specifically reduced in male, but not in female TG rats, while LV diastolic dysfunction was evident in both TG sexes, but LV hypertrophy, increased LV ACE activity, and reduced AMPK activity as evident from AMPK hypophosphorylation were specific to male rats. Sex differences were also observed in vascular and cardiomyocyte function showing different response to acetylcholine and Ca2+-sensitivity of force production, respectively cardiomyocyte functional changes were associated with altered phosphorylation states of cardiac myosin binding protein C and cardiac troponin I phosphorylation in TG males only. Cardiomyocyte passive stiffness was increased in TG animals. On a molecular level titin phosphorylation pattern was altered, though alterations were sex-specific. Thus, also the reduction of PKG expression and activity was more pronounced in TG females. However, cardiomyocyte passive stiffness was restored by PKG and CaMKII treatments in both TG sexes. CONCLUSION: Here we demonstrated divergent sex-specific cardiovascular adaptation to the over-activation of the renin-angiotensin system in the rat. Higher mortality of male TG rats in contrast to female TG rats was observed as well as reduced LV systolic function, whereas females mainly developed HFpEF. Though both sexes developed increased myocardial stiffness to which an impaired titin function contributes to a sex-specific molecular mechanism. The functional derangements of titin are due to a sex-specific divergent regulation of PKG and CaMKII systems.

Acute coronary syndrome associated cardiogenic shock in the catheterization laboratory: peripheral veno-arterial extracorporeal membrane oxygenator management and recommendations.

Cardiogenic shock (CS) in acute coronary syndrome (ACS) is a critical disease with high mortality rates requiring complex treatment to maximize patient survival chances. Emergent coronary revascularization along with circulatory support are keys to saving lives. Mechanical circulatory support may be instigated in severe, yet still reversible instances. Of these, the peripheral veno-arterial extracorporeal membrane oxygenator (pVA-ECMO) is the most widely used system for both circulatory and respiratory support. The aim of our work is to provide a review of our current understanding of the pVA-ECMO when used in the catheterization laboratory in a CS ACS setting. We detail the workings of a Shock Team: pVA-ECMO specifics, circumstances, and timing of implantations and discuss possible complications. We place emphasis on how to select the appropriate patients for potential pVA-ECMO support and what characteristics and parameters need to be assessed. A detailed, stepwise implantation algorithm indicating crucial steps is also featured for practitioners in the catheter laboratory. To provide an overall aspect of pVA-ECMO use in CS ACS we further gave pointers including relevant human resource, infrastructure, and consumables management to build an effective Shock Team to treat CS ACS via the pVA-ECMO method.

Clinical Implications of Fractional Flow Reserve Measured Immediately After Percutaneous Coronary Intervention.

PURPOSE: The purpose of the present study was to find the independent predictors of Fractional Flow Reserve (FFR) measured immediately after percutaneous coronary intervention with drug-eluting stent implantation (post-PCI FFR) and investigate if applying vessel-specific post-PCI FFR cut-off values to predict target vessel failure (TVF), a composite of cardiac death (CD), non-fatal myocardial infarction (MI) and target vessel revascularization (TVR), or a composite of CD and MI ameliorated its predictive power. METHODS: Consecutive patients with post-PCI FFR measurement at our center between 2009 and 2021 were included in this analysis. RESULTS: A total of 434 patients with 500 vessels were included. Median pre-PCI FFR was 0.72 with no difference between LAD and non-LAD vessels. Median post-PCI FFR was 0.87. LAD location, male gender, smaller stent diameter, and lower pre-PCI FFR proved to be significant predictors of a lower post-PCI FFR. On a vessel-level, post-PCI FFR, stent length, and diabetes mellitus proved to be significant predictors of TVF and the composite of CD and MI. The best post-PCI FFR cut-off to predict TVF or a composite of CD and MI was 0.83 in the LAD and 0.91 in non-LAD vessels. CONCLUSION: LAD location is a predictor of a lower post-PCI FFR. Post-PCI FFR is an independent predictor of TVF as well as of the composite of CD and MI. No uniform target post-PCI FFR value exists; different cut-off values may have to be applied in LAD as opposed to non-LAD vessels.

Comparison of Safety of RADial comPRESSion Devices: A Multi-Center Trial of Patent Hemostasis following Percutaneous Coronary Intervention from Conventional Radial Access (RAD-PRESS Trial).

Although radial access is the current gold standard for the implementation of percutaneous coronary interventions (PCI), post-procedural radial compression devices are seldom compared with each other in terms of safety or efficacy. Our group aimed to compare a cost effective and potentially green method to dedicated radial compression devices, with respect to access site complications combined in a device oriented complex endpoint (DOCE), freedom from which served as our primary endpoint. Patients undergoing PCI were randomized to receive either the cost effective or a dedicated device, either of which were removed using patent hemostasis. Twenty-four hours after the procedure, radial artery ultrasonography was performed to evaluate the access site. The primary endpoint was assessed using a non-inferiority framework with a non-inferiority margin of five percentage points, which was considered as the least clinically meaningful difference. The cost-effective technique and the dedicated devices were associated with a comparably low rate of complications (freedom from DOCE: 83.3% vs. 70.8%, absolute risk difference: 12.5%, one-sided 95% confidence interval (CI): 1.11%). Composition of the DOCE (i.e., no complication, hematoma, pseudoaneurysm, and radial artery occlusion) and compression time were also assessed in superiority tests as secondary endpoints. Both the cost-effective technique and the dedicated devices were associated with comparably low rates of complications: p = 0.1289. All radial compression devices performed similarly when considering the time to complete removal of the respective device (120.0 (inter-quartile range: 100.0-142.5) for the vial vs. 120.0 (inter-quartile range: 110.0-180) for the dedicated device arm, with a median difference of [95% CI]: 7.0 [-23.11 to 2.00] min, p = 0.2816). In conclusion, our cost-effective method was found to be non-inferior to the dedicated devices with respect to safety, therefore it is a safe alternative to dedicated radial compression devices, as well as seeming to be similarly effective.

Swimming competitions in the era of COVID-19: Lessons from successfully hosting the International Swimming League.

Background: Organization of mass sport events in the COVID-19 era is utterly complicated. Containments measures, required to avoid a virus outbreak, force athletes to compete under circumstances they never experienced before, most likely having a deleterious effect on their performance. Purpose: We aimed to design a so-called athlete-friendly bubble system for the International Swimming League 2020 event, which is strict enough to avoid a COVID-19 outbreak, but still provides a supportive environment for the athletes. Methods: To avoid the feeling of imprisonment, athletes were permitted to spend a certain amount of time in the parks surrounding the hotels. Such alleviations were possible to apply with strict adherence to the hygienic and social distancing protocols and regular COVID-19 testing. Evaluation of every COVID-19 positive case was key, and if prolonged PCR positivity or false positive PCR result was identified, the unnecessary quarantine was planned to be lifted. Return to play protocol (RTP) was planned, in case of a COVID-19 infection of an athlete inside the bubble. To test, if the athlete-friendly system provided a supportive environment, we evaluated athlete performance. Results: 11,480 PCR tests were performed for 1,421 individuals. 63 COVID-19 positive cases were detected, of which 5 turned out to be clinically insignificant, either because of prolonged PCR positivity or because of a false positive result. 93.1% of the positive cases were detected in the local crew, while no athlete got infected inside the bubble, as the two infected athletes were tested positive upon arrival. RTP was provided for two athletes. 85% of the athletes showed improvement during the bubble and 8 world records were broken. Conclusion: The applied protocol proved to be effective, as no athlete got infected inside the bubble, moreover, the athlete-friendly system supported the athletes to improve their performance.

[Functional assessment of serial coronary lesions and diffuse coronary disease]. / Többszörös coronarialaesiók és diffúz coronariabetegség funkcionális értékelése.

Functional assessment performed during diagnostic coronary angiography has gained an increasing role during the last few decades. Traditional coronary angiography using only anatomical data cannot provide information whether intermediate lesions cause ischaemia or not, and frequently there is no evidence from non-invasive functional tests with appropriate sensitivity and specificity to guide us regarding the localization and severity of ischaemia. Several studies proved the clinical benefit of the use of invasive functional tests. The functional severity of unrevascularized coronary artery disease is correlated with prognosis. It is important to precisely define the lesions causing ischaemia when we plan to improve the blood supply to the heart. The functional assessment of diffuse or serial lesions is not well established. New investigations and methods have been developed such as pullback pressure gradient or instantaneous wave-free ratio intensity besides the well-established and studied functional tests. This could help us find and revascularize the lesions within a coronary vessel primarily responsible for ischaemia and symptoms or, in the case of diffuse disease and no obvious target, to optimize medical therapy. Orv Hetil. 2022; 163(48): 1902-1908.

A Case Series of SARS-CoV-2 Reinfection in Elite Athletes.

OBJECTIVES: The actual frequency and the risk factors of SARS-CoV-2 reinfection is still a matter of intense scientific discussion. In this case series, we report three elite athletes who underwent COVID-19 reinfection with a short time frame. CASE PRESENTATIONS: As a part of contact tracing, three speed skaters (22-, 24-, and 29-year-old males) were found to be SARS-CoV-2 positive by polymerase chain reaction (PCR) tests. Later on, only one of the athletes experienced mild symptoms, such as fatigue, loss of smell and taste and subfebrility, while the other two athletes were asymptomatic. Following the quarantine period, detailed return-to-play examinations, including laboratory testing, ECG, 24-h Holter monitoring, transthoracic echocardiography and cardiac magnetic resonance imaging, revealed no apparent abnormality; therefore, the athletes restarted training. After a median of 74 days, all three athletes presented with typical symptoms of COVID-19, such as fever, marked fatigue and headache. SARS-CoV-2 PCR tests were performed again, showing recurrent positivity. Repeated return-to-play assessments were initiated, finding no relevant abnormality. Athletes were also tested for SARS-CoV-2 anti-nucleoprotein antibody titers, showing only modest increases following the second infection. CONCLUSIONS: We report a small cluster of elite athletes who underwent a PCR-proven SARS-CoV-2 reinfection. According to these findings, athletes may be considered as a high-risk group in terms of recurrent COVID-19.

Treatment of three-vessel disease in light of the results of the FAME-3 study / A háromér-betegség kezelése a FAME-3 vizsgálat eredményeinek tükrében

Previous randomized clinical studies have shown the superiority of coronary artery bypass grafting over percutaneous coronary intervention in the treatment of severe multivessel disease mainly because of a reduced need for repeat revascularization but, in some, a mortality benefit and reduced rate of myocardial infarction were shown among those undergoing surgery. The late breaker multicentric, randomized FAME (Fractional Flow Reserve Versus Angiography in Multivessel Evaluation)-3 study, involving 1500 patients, sought to determine whether fractional flow reserve guided percutaneous coronary intervention with implantation of new-generation drug-eluting stents was non -inferior to present-day coronary bypass surgery with respect to the composite of all-cause death, myocardial infarction, stroke and repeat revascularization at one year. The authors who were particularly active in the FAME-3 trial describe the study setting, the characteristics of the patient population, the procedures, and the results. The FAME-3 study failed to show the non-inferiority of percutaneous coronary intervention to bypass surgery in the treatment of three vessel disease using the predetermined margin. The authors present a detailed analysis of the possible reasons and some important secondary results. These include a lack of significant difference between the two arms with respect to `hard end points' and the significantly higher perioperative morbidity of the surgical group. Albeit our clinical practice should be based on the analysis of the primary end point, informing patients and shared decision making must include these secondary results when individual revascularization strategies are planned.

A Central Role for TRPM4 in Ca2+-Signal Amplification and Vasoconstriction.

Transient receptor potential melastatin-4 (TRPM4) is activated by an increase in intracellular Ca2+ concentration and is expressed on smooth muscle cells (SMCs). It is implicated in the myogenic constriction of cerebral arteries. We hypothesized that TRPM4 has a general role in intracellular Ca2+ signal amplification in a wide range of blood vessels. TRPM4 function was tested with the TRPM4 antagonist 9-phenanthrol and the TRPM4 activator A23187 on the cardiovascular responses of the rat, in vivo and in isolated basilar, mesenteric, and skeletal muscle arteries. TRPM4 inhibition by 9-phenanthrol resulted in hypotension and a decreased heart rate in the rat. TRPM4 inhibition completely antagonized myogenic tone development and norepinephrine-evoked vasoconstriction, and depolarization (high extracellular KCl concentration) evoked vasoconstriction in a wide range of peripheral arteries. Vasorelaxation caused by TRPM4 inhibition was accompanied by a significant decrease in intracellular Ca2+ concentration, suggesting an inhibition of Ca2+ signal amplification. Immunohistochemistry confirmed TRPM4 expression in the smooth muscle cells of the peripheral arteries. Finally, TRPM4 activation by the Ca2+ ionophore A23187 was competitively inhibited by 9-phenanthrol. In summary, TRPM4 was identified as an essential Ca2+-amplifying channel in peripheral arteries, contributing to both myogenic tone and agonist responses. These results suggest an important role for TRPM4 in the circulation. The modulation of TRPM4 activity may be a therapeutic target for hypertension. Furthermore, the Ca2+ ionophore A23187 was identified as the first high-affinity (nanomolar) direct activator of TRPM4, acting on the 9-phenanthrol binding site.

Functional Transient Receptor Potential Ankyrin 1 and Vanilloid 1 Ion Channels Are Overexpressed in Human Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is a common cancer with poor prognosis. Transient Receptor Potential Ankyrin 1 (TRPA1) and Vanilloid 1 (TRPV1) receptors are non-selective cation channels expressed on primary sensory neurons and epithelial and immune cells. TRPV1 mRNA and immunopositivity, as well as TRPA1-like immunoreactivity upregulation, were demonstrated in OSCC, but selectivity problems with the antibodies still raise questions and their functional relevance is unclear. Therefore, here, we investigated TRPA1 and TRPV1 expressions in OSCC and analyzed their functions. TRPA1 and TRPV1 mRNA were determined by RNAscope in situ hybridization and qPCR. Radioactive 45Ca2+ uptake and ATP-based luminescence indicating cell viability were measured in PE/CA-PJ41 cells in response to the TRPA1 agonist allyl-isothiocyanate (AITC) and TRPV1 agonist capsaicin to determine receptor function. Both TRPA1 and TRPV1 mRNA are expressed in the squamous epithelium of the human oral mucosa and in PE/CA-PJ41 cells, and their expressions are significantly upregulated in OSCC compared to healthy mucosa. TRPA1 and TRPV1 activation (100 µM AITC, 100 nM capsaicin) induced 45Ca2+-influx into PE/CA-PJ41 cells. Both AITC (10 nM-5 µM) and capsaicin (100 nM-45 µM) reduced cell viability, reaching significant decrease at 100 nM AITC and 45 µM capsaicin. We provide the first evidence for the presence of non-neuronal TRPA1 receptor in the OSCC and confirm the expression of TRPV1 channel. These channels are functionally active and might regulate cancer cell viability.

Correlation and Relative Prognostic Value of Fractional Flow Reserve and Pd/Pa of Nonculprit Lesions in ST-Segment-Elevation Myocardial Infarction.

BACKGROUND: The applicability of resting indices to guide noninfarct-related artery revascularization in ST-elevation myocardial infarction is unknown. METHODS: We analyzed the correlation and prognostic value of fractional flow reserve (FFR) and resting distal coronary to aortic pressure ratio (Pd/Pa) in all patients of the Compare-Acute trial in whom, after successful primary percutaneous coronary intervention, the noninfarct-related artery was interrogated by both and treated medically. The treating cardiologist was blinded to these values. The primary end point was the composite of target vessel (interrogated noninfarct-related artery) related nonfatal target vessel myocardial infarction and target vessel repeat revascularization at 36 months. RESULTS: Five hundred seventeen patients (665 vessels) were included. On receiver-operating characteristic analysis, the optimal Pd/Pa cut off for FFR≤0.80 was 0.905 (C statistic: 0.894). The diagnostic accuracy of Pd/Pa was 80.15% (95% CI, 76.91%-83.12%) with respect to FFR. During the 36-month follow-up, 130 target vessel revascularization and 14 target vessel myocardial infarction occurred. FFR and Pd/Pa had a diagnostic accuracy to predict these events of 62.86% (95% CI, 59.06%-66.54%) and 56.84% (95% CI, 52.98%-60.64%), respectively (P=0.20). When they were discrepant, FFR was significantly better than Pd/Pa in identifying which vessels could be safely deferred (P=0.048). CONCLUSIONS: Immediately after successful primary percutaneous coronary intervention, resting Pd/Pa has a diagnostic accuracy of 80% with respect to FFR measured in the noninfarct-related artery. FFR is not significantly superior in predicting target vessel myocardial infarction and target vessel revascularization during 36 months of follow-up but, in case FFR and Pd/Pa are discrepant, FFR is superior in identifying which nonculprit vessels can be safely deferred. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01399736.

Cerebral venous congestion exacerbates cerebral microhemorrhages in mice.

Cerebral microhemorrhages (CMHs; microbleeds), which are small focal intracerebral hemorrhages, importantly contribute to the pathogenesis of cognitive decline and dementia in older adults. Although recently it has been increasingly recognized that the venous side of the cerebral circulation likely plays a fundamental role in the pathogenesis of a wide spectrum of cerebrovascular and brain disorders, its role in the pathogenesis of CMHs has never been studied. The present study was designed to experimentally test the hypothesis that venous congestion can exacerbate the genesis of CMHs. Increased cerebral venous pressure was induced by internal and external jugular vein ligation (JVL) in C57BL/6 mice in which systemic hypertension was induced by treatment with angiotensin II plus L-NAME. Histological analysis (diaminobenzidine staining) showed that mice with JVL developed multiple CMHs. CMHs in mice with JVL were often localized adjacent to veins and venules and their morphology was consistent with venous origin of the bleeds. In brains of mice with JVL, a higher total count of CMHs was observed compared to control mice. CMHs were distributed widely in the brain of mice with JVL, including the cortical gray matter, brain stem, the basal ganglia, subcortical white matter, cerebellum, and the hippocampi. In mice with JVL, there were more CMHs predominantly in cerebral cortex, brain stem, and cerebellum than in control mice. CMH burden, defined as total CMH volume, also significantly increased in mice with JVL. Thus, cerebral venous congestion can exacerbate CMHs. These observations have relevance to the pathogenesis of cognitive impairment associated with right heart failure as well as elevated cerebral venous pressure due to jugular venous reflux in older adults.

The aging venous system: from varicosities to vascular cognitive impairment.

Aging-induced pathological alterations of the circulatory system play a critical role in morbidity and mortality of older adults. While the importance of cellular and molecular mechanisms of arterial aging for increased cardiovascular risk in older adults is increasingly appreciated, aging processes of veins are much less studied and understood than those of arteries. In this review, age-related cellular and morphological alterations in the venous system are presented. Similarities and dissimilarities between arterial and venous aging are highlighted, and shared molecular mechanisms of arterial and venous aging are considered. The pathogenesis of venous diseases affecting older adults, including varicose veins, chronic venous insufficiency, and deep vein thrombosis, is discussed, and the potential contribution of venous pathologies to the onset of vascular cognitive impairment and neurodegenerative diseases is emphasized. It is our hope that a greater appreciation of the cellular and molecular processes of vascular aging will stimulate further investigation into strategies aimed at preventing or retarding age-related venous pathologies.

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.

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.

Prognosis of the non-ST elevation myocardial infarction complicated with early ventricular fibrillation at higher age.

Early ventricular fibrillation (EVF) predicts mortality in ST-segment elevation myocardial infarction (STEMI) patients. Data are lacking about prognosis and management of non-ST-segment elevation myocardial infarction (NSTEMI) EMI with EVF, especially at higher age. In the daily clinical practice, there is no clear prognosis of patients surviving EVF. The present study aimed to investigate the risk factors and factors influencing the prognosis of NSTEMI patients surviving EVF, especially at higher age. Clinical data, including 30-day and 1-year mortality of 6179 NSTEMI patients, were examined; 2.44% (n=151) survived EVF and were further analyzed using chi-square test and uni- and multivariate analyses. Patients were divided into two age groups below and above the age of 70 years. Survival time was compared with Kaplan-Meier analysis. EVF was an independent risk factor for mortality in NSTEMI patients below (HR: 2.4) and above the age of 70 (HR: 2.1). Mortality rates between the two age groups of NSTEMI patients with EVF did not differ significantly: 30-day mortality was 24% vs 40% (p=0.2709) and 1-year mortality was 39% vs 55% (p=0.2085). Additional mortality after 30 days to 1 year was 15% vs 14.6% (p=0.9728). Clinical characteristics of patients with EVF differed significantly from those without in both age groups. EVF after revascularization-within 48 h-had 11.2 OR for 30-day mortality above the age of 70. EVF in NSTEMI was an independent risk factor for mortality in both age groups. Invasive management and revascularization of NSTEMI patients with EVF is highly recommended. Closer follow-up and selection of patients (independent of age) for ICD implantation in the critical first month is essential.

Omecamtiv mecarbil evokes diastolic dysfunction and leads to periodic electromechanical alternans.

Omecamtiv mecarbil (OM) is a promising novel drug for improving cardiac contractility. We tested the therapeutic range of OM and identified previously unrecognized side effects. The Ca2+ sensitivity of isometric force production (pCa50) and force at low Ca2+ levels increased with OM concentration in human permeabilized cardiomyocytes. OM (1 µM) slowed the kinetics of contractions and relaxations and evoked an oscillation between normal and reduced intracellular Ca2+ transients, action potential lengths and contractions in isolated canine cardiomyocytes. Echocardiographic studies and left ventricular pressure-volume analyses demonstrated concentration-dependent improvements in cardiac systolic function at OM concentrations of 600-1200 µg/kg in rats. Administration of OM at a concentration of 1200 µg/kg was associated with hypotension, while doses of 600-1200 µg/kg were associated with the following aspects of diastolic dysfunction: decreases in E/A ratio and the maximal rate of diastolic pressure decrement (dP/dtmin) and increases in isovolumic relaxation time, left atrial diameter, the isovolumic relaxation constant Tau, left ventricular end-diastolic pressure and the slope of the end-diastolic pressure-volume relationship. Moreover, OM 1200 µg/kg frequently evoked transient electromechanical alternans in the rat in vivo in which normal systoles were followed by smaller contractions (and T-wave amplitudes) without major differences on the QRS complexes. Besides improving systolic function, OM evoked diastolic dysfunction and pulsus alternans. The narrow therapeutic window for OM may necessitate the monitoring of additional clinical safety parameters in clinical application.

Effects of Low-Level Tragus Stimulation on Endothelial Function in Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Autonomic dysregulation in heart failure with reduced ejection fraction plays a major role in endothelial dysfunction. Low-level tragus stimulation (LLTS) is a novel, noninvasive method of autonomic modulation. METHODS AND RESULTS: We enrolled 50 patients with heart failure with reduced ejection fraction (left ventricular ejection fraction of ≤40%) in a randomized, double-blinded, crossover study. On day 1, patients underwent 60 minutes of LLTS with a transcutaneous stimulator (20 Hz, 200 µs pulse width) or sham (ear lobule) stimulation. Macrovascular function was assessed using flow-mediated dilatation in the brachial artery and cutaneous microcirculation with laser speckle contrast imaging in the hand and nail bed. On day 2, patients were crossed over to the other study arm and underwent sham or LLTS; vascular tests were repeated before and after stimulation. Compared with the sham, LLTS improved flow-mediated dilatation by increasing the percent change in the brachial artery diameter (from 5.0 to 7.5, LLTS on day 1, P = .02; and from 4.9 to 7.1, LLTS on day 2, P = .003), compared with no significant change in the sham group (from 4.6 to 4.7, P = .84 on day 1; and from 5.6 to 5.9 on day 2, P = .65). Cutaneous microcirculation in the hand showed no improvement and perfusion of the nail bed showed a trend toward improvement. CONCLUSIONS: Our study demonstrated the beneficial effects of acute neuromodulation on macrovascular function. Larger studies to validate these findings and understand mechanistic links are warranted.

Empagliflozin improves endothelial and cardiomyocyte function in human heart failure with preserved ejection fraction via reduced pro-inflammatory-oxidative pathways and protein kinase Gα oxidation.

AIMS: Sodium-glucose-cotransporter-2 inhibitors showed favourable cardiovascular outcomes, but the underlying mechanisms are still elusive. This study investigated the mechanisms of empagliflozin in human and murine heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: The acute mechanisms of empagliflozin were investigated in human myocardium from patients with HFpEF and murine ZDF obese rats, which were treated in vivo. As shown with immunoblots and ELISA, empagliflozin significantly suppressed increased levels of ICAM-1, VCAM-1, TNF-α, and IL-6 in human and murine HFpEF myocardium and attenuated pathological oxidative parameters (H2O2, 3-nitrotyrosine, GSH, lipid peroxide) in both cardiomyocyte cytosol and mitochondria in addition to improved endothelial vasorelaxation. In HFpEF, we found higher oxidative stress-dependent activation of eNOS leading to PKGIα oxidation. Interestingly, immunofluorescence imaging and electron microscopy revealed that oxidized PKG1α in HFpEF appeared as dimers/polymers localized to the outer-membrane of the cardiomyocyte. Empagliflozin reduced oxidative stress/eNOS-dependent PKGIα oxidation and polymerization resulting in a higher fraction of PKGIα monomers, which translocated back to the cytosol. Consequently, diminished NO levels, sGC activity, cGMP concentration, and PKGIα activity in HFpEF increased upon empagliflozin leading to improved phosphorylation of myofilament proteins. In skinned HFpEF cardiomyocytes, empagliflozin improved cardiomyocyte stiffness in an anti-oxidative/PKGIα-dependent manner. Monovariate linear regression analysis confirmed the correlation of oxidative stress and PKGIα polymerization with increased cardiomyocyte stiffness and diastolic dysfunction of the HFpEF patients. CONCLUSION: Empagliflozin reduces inflammatory and oxidative stress in HFpEF and thereby improves the NO-sGC-cGMP-cascade and PKGIα activity via reduced PKGIα oxidation and polymerization leading to less pathological cardiomyocyte stiffness.

Chitotriosidase gene polymorphisms and mutations limit the determination of chitotriosidase expression in sarcoidosis.

Serum chitotriosidase (CTO) activity was proposed as a biomarker in sarcoidosis being potentially useful in diagnostics. Nevertheless, a common duplication polymorphism (c.1049_1072dup24, Dup24) of the CTO gene influences CTO activity and thereby compromises its use in sarcoidosis. Here we aimed to substitute CTO activity with CTO concentration to prevent the confounding effect of Dup24. CTO activity, concentration and genetic backgrounds were determined in 80 histopathology proven sarcoidosis patients and 133 healthy individuals. CTO activities were lower in healthy individuals and sarcoidosis patients heterozygous for Dup24 mutation (472 ± 367 mU/L, n = 49; 2300 ± 2105 mU/L, n = 29) than in homozygous wild types (838 ± 856 mU/L, n = 81; 5125 ± 4802 mU/L, n = 48; p < 0.001, respectively). Sera of Dup24 homozygous individuals had no CTO activity. CTO concentrations were also lower in healthy individuals and sarcoidosis patients heterozygous for Dup24 mutation (7.2 ± 1.9 µg/L, n = 11; 63.16 ± 56.5 µg/L, n = 29) than in homozygous wild types (18.9 ± 13.0 µg/L, n = 36; 157.1 ± 132.4 µg/L, n = 47, p < 0.001, respectively) suggestive for an interaction between Dup24 mutation and CTO concentration determinations. We also identified a healthy Hungarian male subject without CTO activity carrying a rare mutation (c.(965_993)del), which mutation has been considered unique for Cypriot population to date. Taken together, CTO concentration determination does not add to the CTO activity measurement when CTO is used as a biomarker in sarcoidosis. Therefore, genotyping of CTO gene should be involved in the interpretation of laboratory findings.