Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Deletion but Not Inhibition of Extracellular PCSK9 Reduces Infarct Sizes Ex Vivo but Not In Vivo.

Hypoxia upregulates PCSK9 expression in the heart, and PCSK9 affects the function of myocytes. This study aimed to investigate the impact of PCSK9 on reperfusion injury in rats and mice fed normal or high-fat diets. Either the genetic knockout of PCSK9 (mice) or the antagonism of circulating PCSK9 via Pep2-8 (mice and rats) was used. Isolated perfused hearts were exposed to 45 min of ischemia followed by 120 min of reperfusion. In vivo, mice were fed normal or high-fat diets (2% cholesterol) for eight weeks prior to coronary artery occlusion (45 min of ischemia) and reperfusion (120 min). Ischemia/reperfusion upregulates PCSK9 expression (rats and mice) and releases it into the perfusate. The inhibition of extracellular PCSK9 does not affect infarct sizes or functional recovery. However, genetic deletion largely reduces infarct size and improves post-ischemic recovery in mice ex vivo but not in vivo. A high-fat diet reduced the survival rate during ischemia and reperfusion, but in a PCSK9-independent manner that was associated with increased plasma matrix metalloproteinase (MMP)9 activity. PCSK9 deletion, but not the inhibition of extracellular PCSK9, reduces infarct sizes in ex vivo hearts, but this effect is overridden in vivo by factors such as MMP9.

Electrocardiographic Changes Associated with Early Repolarization Pattern in Healthy Young Males.

Background and Objectives: Early repolarization pattern (ERP) has recently been shown to be related with an increased risk of ventricular arrhythmias in susceptible individuals. Materials and Methods: We studied the ERP-associated ECG changes, with potential clinical relevance, in 220 young (age 22.1 ± 1.6 years), healthy, male subjects using 12-lead ECG recordings. A total of 38 subjects (17.3%) fulfilled the diagnostic criteria for ERP, and a total of 90 ECG characteristics were compared between the groups of subjects with and without ERP. Results: None of the ECGs were pathological, and 22 ECG parameters differed significantly (p < 0.05) between the subjects with and without ERP. Among them, the P wave-related parameters (e.g., average P wave duration: 101.5 ± 9.2 ms vs. 106.8 ± 9.9 ms, p = 0.004) and the presence of fragmented QRS complexes (67.6% vs. 92.1%, p = 0.002) revealed a potential propensity for atrial and ventricular arrhythmogenesis. The time-domain parameters of repolarization, those not corrected for QRS duration, showed shorter values (e.g., Tpeak-Tend interval: 70.9 ± 8.1 ms vs. 67.8 ± 8.0 ms, p = 0.036), reflecting the accelerated repolarization. Conclusions: Certain ECG characteristics seem to be more associated with ERP. The clinical significance of this finding at the individual level needs further prospective investigations.

Inhibition of pro-inflammatory myeloid cell responses by short-term S100A9 blockade improves cardiac function after myocardial infarction.

AIMS: Neutrophils have both detrimental and beneficial effects in myocardial infarction (MI), but little is known about the underlying pathways. S100A8/A9 is a pro-inflammatory alarmin abundantly expressed in neutrophils that is rapidly released in the myocardium and circulation after myocardial ischaemia. We investigated the role of S100A8/A9 in the innate immune response to MI. METHODS AND RESULTS: In 524 patients with acute coronary syndrome (ACS), we found that high plasma S100A8/A9 at the time of the acute event was associated with lower left ventricular ejection fraction (EF) at 1-year and increased hospitalization for heart failure (HF) during follow-up. In wild-type C57BL/6 mice with MI induced by permanent coronary artery ligation, treatment with the S100A9 blocker ABR-238901 during the inflammatory phase of the immune response inhibited haematopoietic stem cell proliferation and myeloid cell egression from the bone marrow. The treatment reduced the numbers of neutrophils and monocytes/macrophages in the myocardium, promoted an anti-inflammatory environment, and significantly improved cardiac function compared with MI controls. To mimic the clinical scenario, we further confirmed the effects of the treatment in a mouse model of ischaemia/reperfusion. Compared with untreated mice, 3-day ABR-238901 treatment significantly improved left ventricular EF (48% vs. 35%, P = 0.002) and cardiac output (15.7 vs. 11.1 mL/min, P = 0.002) by Day 21 post-MI. CONCLUSION: Short-term S100A9 blockade inhibits inflammation and improves cardiac function in murine models of MI. As an excessive S100A8/A9 release is linked to incident HF, S100A9 blockade might represent a feasible strategy to improve prognosis in ACS patients.

Exercise-Induced Electrocardiographic Changes in Healthy Young Males with Early Repolarization Pattern.

Background: Exercise-induced modifications in ECG parameters among individuals with an early repolarization pattern (ERP) have not been evaluated in detail. We aimed to assess this phenomenon, with potential associations with arrhythmogenesis. Methods: Twenty-three young, healthy males with ERP (ERP+) participated in this study, alongside a control group, which consisted of nineteen healthy males without ERP (ERP-). ECGs at baseline, at peak exercise (Bruce protocol), and during the recovery phase were analyzed and compared between the two groups. Results: The treadmill test demonstrated strong cardiovascular fitness, with similar chronotropic and pressor responses in both groups. In the baseline ECGs, the QRS complex and the QT interval were shorter in the ERP+ group. During exercise, the P-wave duration was significantly longer and the QRS was narrower in the ERP+ group. In the recovery phase, there was a longer P wave and a narrower QRS in the ERP+ group. During the treadmill test, the J wave disappeared or did not meet the criteria required for ERP diagnosis. Conclusions: The slowed intra-atrial conduction found during exercise could be predictive of atrial arrhythmogenesis in the setting of ERP. The disappearing of J waves during exercise, due to increased sympathetic activity, has potential clinical significance.

S100A8∕A9 is a valuable biomarker and treatment target to detect and modulate neutrophil involvement in myocardial infarction.

Myocardial infarction (MI) leads to irreversible ischemic damage of the heart muscle and is the leading cause of heart failure. The ischemic cardiac injury triggers a potent local and systemic immune response. In the acute phase post-MI, neutrophils infiltrate the myocardium in large numbers and induce further cardiomyocyte death, expanding the infarcted area. The alarmin S100A8∕A9 is a proinflammatory mediator primarily produced by myeloid cells, with an emerging role in MI. We previously demonstrated that short-term inhibition of S100A8∕A9 during the inflammatory phase of the immune response to MI improves long-term cardiac function. In the present study, we investigated the effects of S100A8∕A9 blockade on myocardial inflammation and post-ischemic myocardial injury in a mouse model of coronary artery ligation. Immunohistochemical (IHC) staining revealed that the presence of S100A9 is strongly correlated with neutrophil infiltration in the myocardium on days 1 and 3 post-MI. A 3-day treatment with the S100A8∕A9 blocker ABR-238901 starting immediately after MI decreased the number of neutrophils and S100A9 presence in the myocardium and had a positive impact on cardiac damage, reducing infarction size. These findings promote S100A9 as an IHC biomarker of neutrophil infiltration and a promising immunomodulatory target to regulate neutrophil recruitment, reduce ischemic injury and promote long-term beneficial cardiac recovery after MI.

Prognostic Value of Lung Ultrasound in Aortic Stenosis.

Background: Aortic stenosis (AS) is the most common primary valve lesion requiring intervention in Europe and North America. It has a prolonged subclinical period during which, as AS worsens, left ventricular adaptation becomes inadequate and impaired systolic and/or diastolic dysfunction may lead to overt heart failure (HF). The development of HF is an inflexion point in the natural history of AS. Pulmonary congestion is a cardinal feature in HF, and lung ultrasound (LUS) evaluation of B-lines has been proposed as a simple, noninvasive tool to assess pulmonary congestion. Aim: To assess the presence and the prognostic value of sonographic pulmonary congestion in patients with moderate or severe AS. Methods: 75 consecutive patients (39 women, mean age 73.85 ± 7.7 years) with moderate or severe AS were enrolled. All patients underwent comprehensive echocardiography and LUS with the 28 scanning-site assessment. Patients were followed-up for 13.4 ± 6 months to establish the prognostic value of LUS. A composite endpoint of death (of any cause), hospitalization for HF and intensification of loop diuretic therapy was considered. Results: We found a severe degree of B-lines (≥30) in 29.33% of patients. The number of B-lines correlated with the estimated pulmonary artery systolic pressure (p < 0.001, r = 0.574) and increased along with NYHA class (p < 0.05, rho = 0.383). At multivariable analysis, B-lines ≥30, and mean gradient were the independent predictors of events [B-lines: 2.79 (CI 1.03-7.54), p = 0.04; mean gradient: 1.04 (CI 1.01-1.07), p = 0.004]. Conclusion: Evaluation of B-lines is a simple, highly feasible method to detect pulmonary congestion in AS. The number of B-lines correlates with the hemodynamic changes caused by AS and with the functional status of patients. A severe degree of sonographic pulmonary congestion is associated with an increased risk of adverse events.

Applicability of lung ultrasound in the assessment of COVID-19 pneumonia: Diagnostic accuracy and clinical correlations.

BACKGROUND: The purpose of this study was to assess the diagnostic accuracy of lung ultrasound (LUS) in determining the severity of coronavirus disease 2019 (COVID-19) pneumonia compared with thoracic computed tomography (CT) and establish the correlations between LUS score, inflammatory markers, and percutaneous oxygen saturation (SpO2). METHODS: This prospective observational study, conducted at Târgu-Mureș Pulmonology Clinic included 78 patients with confirmed severe acute respiratory syndrome coronavirus-2 infection via nasopharyngeal real-time-polymerase chain reaction (RT-PCR) (30 were excluded). Enrolled patients underwent CT, LUS, and blood tests on admission. Lung involvement was evaluated in 16 thoracic areas, using AB1 B2 C (letters represent LUS pattern) scores ranging 0-48. RESULTS: LUS revealed bilateral B-lines (97.8%), pleural irregularities with thickening/discontinuity (75%), and subpleural consolidations (70.8%). Uncommon sonographic patterns were alveolar consolidations with bronchogram (33%) and pleural effusion (2%). LUS score cutoff values of ≤14 and > 22 predicted mild COVID-19 (sensitivity [Se] = 84.6%; area under the curve [AUC] = 0.72; P = 0.002) and severe COVID-19 (Se = 50%, specificity (Sp) = 91.2%, AUC = 0.69; P = 0.02), respectively, and values > 29 predicted the patients' transfer to the intensive care unit (Se = 80%, Sp = 97.7%). LUS score positively correlated with CT score (r = 0.41; P = 0.003) and increased with the decrease of SpO2 (r = -0.49; P = 0.003), with lymphocytes decline (r = -0.52; P = 0.0001). Patients with consolidation patterns had higher ferritin and C-reactive protein than those with B-line patterns (P = 0.01; P = 0.03). CONCLUSIONS: LUS is a useful, non-invasive and effective tool for diagnosis, monitoring evolution, and prognostic stratification of COVID-19 patients.

Comparative study of echocardiographic parameters in young males with early repolarization pattern / Korai repolarizációs mintázatot mutató fiatal férfiak echokardiográfiás jellemzoinek összehasonlító vizsgálata.

Összefoglaló. Bevezetés: Az EKG-n megjeleno korai repolarizációs mintázat diagnosztikai kritériumai és klinikai jelentosége elsosorban az elmúlt évtizedben került tisztázásra, ugyanakkor viszonylag kevés vizsgálat foglalkozott mind ez idáig a korai repolarizációs mintázathoz kötheto esetleges strukturális szívelváltozások felderítésével. Módszer: Egy prospektív vizsgálat során azonosított 30, korai repolarizációs mintázatot mutató fiatal férfi (átlagéletkor: 22,5 ± 1,5 év) echokardiográfiás paramétereit hasonlítottuk össze egy 32 fobol álló (átlagéletkor: 22,3 ± 1,9 év) megfeleltetett kontrollcsoport azonos jellemzoivel. A hagyományos paraméterek mérésén túlmenoen, szöveti Doppler- és 'strain' (deformáció - speckle tracking módszerrel) vizsgálatot is végeztünk, összesen 35 jellemzot követve. A paraméterek összehasonlítása kétmintás t-próba, illetve khi-négyzet-próba segítségével történt (szignifikancia: p<0,05). Eredmények: Nem találtunk patológiás elváltozásokat egyik személy esetében sem, és a két csoport között csupán két paraméter tekintetében fedeztünk fel szignifikáns eltérést. A korai repolarizációs mintázatot mutató csoportban kisebbnek bizonyult a bal kamra végsystolés térfogata (37,6 ± 15,2 ml vs. 45,5 ± 13,4 ml; p = 0,037), illetve gyakoribbnak találtuk az enyhe mitralis regurgitatio elofordulását (41,4% vs. 6,5%; p<0,001). Következtetés: A korai repolarizációs mintázatot mutató fiatal férfiak esetén kimutathatók bizonyos echokardiográfiás jellegzetességek. Ezek idobeli alakulásának, illetve prognosztikai, aritmológiai jelentoségének megítélése további, longitudinális követést igényel. Orv Hetil. 2021; 162(19): 741-745. INTRODUCTION: The diagnostic criteria and clinical significance of early repolarization pattern on ECG were clarified mainly in the last decade. However, there are only a few studies published on the exploration of cardiac structural changes underlying early repolarization pattern. METHOD: We compared the echocardiographic parameters of 30 young males with early repolarization pattern (mean age: 22.5 ± 1.5 years), who were identified during a prospective survey, with the same parameters of a matched control group consisting of 32 young males (mean age: 22.3 ± 1.9 years). Beyond measuring the conventional parameters, tissue Doppler and strain measures (speckle tracking) were obtained. Comparison of parameters was performed using t-test and chi-square test (significancy: p<0.05). RESULTS: There were no pathological changes in any person, and we found significant difference between the two groups only in the case of two parameters. In the early repolarization pattern group, the left ventricular end-systolic volume was smaller (37.6 ± 15.2 ml vs. 45.5 ± 13.4 ml; p = 0.037) and the presence of mild mitral regurgitation was more frequent (41.4% vs. 6.5%; p<0.001). CONCLUSION: In young males with early repolarization pattern, we managed to demonstrate the existence of certain echocardiographic features. The assessment of their time course, prognostic and arrhythmological significance requires a longer follow-up. Orv Hetil. 2021; 162(19): 741-745.

The Prognostic Value of Lung Ultrasound in Patients With Newly Diagnosed Heart Failure With Preserved Ejection Fraction in the Ambulatory Setting.

Background: Heart failure with preserved ejection fraction (HFpEF) is a growing healthcare burden, and its prevalence is steadily increasing. Lung ultrasound (LUS) is a promising screening and prognostic tool in the heart failure population. However, more information on its value in predicting outcome is needed. Aims: The aim of our study was to assess the prognostic performance of LUS B-lines compared to traditional and novel clinical and echocardiographic parameters and natriuretic peptide levels in patients with newly diagnosed HFpEF in an ambulatory setting. Methods: In our prospective cohort study, all ambulatory patients with clinical suspicion of HFpEF underwent comprehensive echocardiography, lung ultrasound and NT-proBNP measurement during their first appointment at our cardiology outpatient clinic. Our endpoint was a composite of worsening heart failure symptoms requiring hospitalization or loop diuretic dose escalation and death. Results: We prospectively enrolled 75 consecutive patients with HFpEF who matched our inclusion and exclusion criteria. We detected 11 events on a 26 ± 10-months follow-up. We found that the predictive value of B-lines is similar to the predictive value of NT-proBNP (AUC 0.863 vs. 0.859), with the best cut-off at >15 B-lines. Having more B-lines than 15 significantly increased the likelihood of adverse events with a hazard ratio of 20.956 (p = 0.004). The number of B-lines remained an independent predictor of events at multivariate modeling. Having more than 15 B-lines lines was associated with a significantly worse event-free survival (Log-rank: 16.804, p < 0.001). Conclusion: The number of B-lines seems to be an independent prognostic factor for adverse outcomes in HFpEF. Since it is an easy-to-learn, feasible and radiation-free method, it may add substantial value to the commonly used diagnostic and risk stratification models.

Serum Osteoprotegerin and Carotid Intima-Media Thickness Are Related to High Arterial Stiffness in Heart Failure with Reduced Ejection Fraction.

Arterial stiffness (AS) is a complex vascular phenomenon with consequences for central hemodynamics and left-ventricular performance. Circulating biomarkers have been associated with AS; however, their value in heart failure is poorly characterized. Our aim was to evaluate the clinical and biomarker correlates of AS in the setting of heart failure with reduced ejection fraction (HFrEF). In 78 hospitalized, hemodynamically stable patients (20 women, 58 men, mean age 65.8 ± 1.41 years) with HFrEF, AS was measured using aortic pulse wave velocity (PWV). Serum OPG, RANKL, sclerostin, and DKK-1 were determined, and the relationships between the clinical variables, vascular-calcification-related biomarkers, and PWV were evaluated by correlation analysis and linear and logistic regression models. OPG and the OPG/RANKL ratio were significantly higher in the group of patients (n = 37, 47.4%) with increased PWV (>10 m/s). PWV was positively correlated with age, left-ventricular ejection fraction, and carotid intima-media thickness (cIMT), and negatively correlated with the glomerular filtration rate. OPG and cIMT were significantly associated with PWV in the logistic regression models when adjusted for hypertension, EF, and the presence of atherosclerotic manifestations. Elevated serum OPG, together with cIMT, were significantly related to increased AS in the setting of HFrEF.

Elevated CA-125 as Humoral Biomarker of Congestive Heart Failure: Illustrative Cases and a Short Review of Literature.

Despite the recent, remarkable achievements in cardiology, heart failure (HF) remains a major public health problem due to its increasing prevalence, frequent hospitalizations, and significant mortality. Humoral biomarkers in HF are capable to reflect different aspects of the cardiac morpho-functional changes and the related pathophysiological processes and could have important diagnostic, prognostic, and therapeutical roles. CA-125 is a well-known tumor marker (mainly for ovarian cancer), and also a useful, but less applied cardiac biomarker. Practical aspects, possible pitfalls related with increased CA-125 levels are illustrated by two cases, both with HF, with the biomarker determined for other reasons and having high levels in the context of the cardiac decompensation. The paper presents a short review of the main biochemical, pathophysiological, and clinical data linked to CA-125, with special accent on its utility in patients with HF.

Autonomic influences related to frequent ventricular premature beats in patients without structural heart disease.

To study the possible role of autonomic influences on the occurrence of frequent premature ventricular beats (VPBs) in subjects without structural heart disease.24-hour Holter ECG recordings (≥1500 VPBs/d, sinus rhythm) of 20 symptomatic patients (9 women, 11 men, mean age 58.9 years) without structural heart disease were used for the study. The circadian distribution pattern of VPBs was studied (paired t test) by dividing the day into 3 periods (16:00-22:00-06:00-16:00), and correlations were analyzed between the absolute (ln transformed) and relative (% of total beats) average hourly numbers of VPBs and the hourly mean values of global and vagal time domain parameters of heart rate variability (Pearson correlation).No significant (P > .3 for every comparison) tendency for circadian distribution of VPBs was found. However, VPBs showed a significant correlation with rMSSD (r = 0.51 and P = .02 for the relative number), which became even stronger if VPBs were > 8000/d (r = 0.65 and P = .04 for both numbers).The significant correlation between the number of VPBs and a vagally mediated parameter underlines the triggering/permitting effect of parasympathetic tone on ventricular ectopy. This fact suggests that initiation of beta-blocker therapy could not be recommended routinely in these patients.