Ventricular Contractile Function Research Articles

Global Longitudinal Strain for the Early Detection of Chemotherapy-Induced Cardiotoxicity: A Systematic Review and Meta-analysis

AimsLeft ventricular ejection fraction is used to monitor patients undergoing cardiotoxic chemotherapy. A decrease in left ventricular ejection fraction represents a relatively late stage of systolic involvement. Global longitudinal strain has been studied to detect early changes in left ventricular myocardial contractile function. The aim of the present study was to evaluate the global longitudinal strain measurement in the early detection of cardiotoxicity induced by cardiotoxic chemotherapeutic agents. Materials and methodsA study search strategy based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was carried out to report systematic reviews. A search on PubMed, EMBASE, Web of Science and SCOPUS was carried out using the following keywords: ‘echocardiography’ and ‘cardiotoxicity’ and their variations, without language or date restrictions (until March 2021). ResultsIn total, 4873 articles were identified for title and abstract analysis. The systematic review included 10 studies comprising 661 patients with cancer, including mainly breast cancer and haematological malignancies, mainly treated with anthracyclines. The meta-analysis included four studies: patients with cardiotoxicity showed a reduction in strain, compared with baseline, 14.13% greater than patients without cardiotoxicity (95% confidence interval 5.07–23.19; P < 0.01). No heterogeneity was observed between studies (I2 = 0). ConclusionThe meta-analysis showed that strain is a tool with proper predictive capacity for the detection of cardiotoxicity.

Progressive Reduction in Right Ventricular Contractile Function Attributable to Altered Actin Expression in an Aging Mouse Model of Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is an inherited genetic disorder of desmosomal dysfunction, and PKP2 (plakophilin-2) has been reported to be the most common disease-causing gene when mutation-positive. In the early concealed phase, the ACM heart is at high risk of sudden cardiac death before cardiac remodeling occurs because of mistargeted ion channels and altered Ca2+ handling. However, the results of pathogenic PKP2 variants on myocyte contraction in ACM pathogenesis remain unknown. We studied the outcomes of a human truncating variant of PKP2 on myocyte contraction using a novel knock-in mouse model with insertion of thymidine in exon 5 of Pkp2, which mimics a familial case of ACM (PKP2-L404fsX5). We used serial echocardiography, electrocardiography, blood pressure measurements, histology, cardiomyocyte contraction, intracellular calcium measurements, and gene and protein expression studies. Serial echocardiography of Pkp2 heterozygous (Pkp2-Het) mice revealed progressive failure of the right ventricle (RV) in animals older than 3 months. By contrast, left ventricular function remained normal. ECGs of 6-month-old anesthetized Pkp2-Het mice showed normal baseline heart rates and QRS complexes. Cardiac responses to β-adrenergic agonist isoproterenol (2 mg/kg) plus caffeine (120 mg/kg) were also normal. However, adrenergic stimulation enhanced the susceptibility of Pkp2-Het hearts to tachyarrhythmia and sudden cardiac death. Histological staining showed no significant fibrosis or adipocyte infiltration in the RVs and left ventricles of 6- and 12-month-old Pkp2-Het hearts. Contractility assessment of isolated myocytes demonstrated progressively reduced Pkp2-Het RV cardiomyocyte function consistent with RV failure measured by echocardiography. However, aging Pkp2-Het and control RV myocytes loaded with intracellular Ca2+ indicator Fura-2 showed comparable Ca2+ transients. Western blotting of Pkp2-RV homogenates revealed a 40% decrease in actin, whereas actin immunoprecipitation followed by a 2,4-dinitrophenylhydrazine staining showed doubled oxidation level. This correlated with a 39% increase in troponin-I phosphorylation. In contrast, Pkp2-Het left ventricular myocytes had normal contraction, actin expression and oxidation, and troponin-I phosphorylation. Last, Western blotting of cardiac biopsies revealed that actin expression was 40% decreased in RVs of patients with end-stage ACM. During the early concealed phase of ACM, reduced actin expression drives loss of RV myocyte contraction, contributing to progressive RV dysfunction.

Speckle-Tracking Analysis in Fetuses With Tetralogy of Fallot: Evaluation of Right and Left Ventricular Contractility and Left Ventricular Function.

This study examines fetuses with tetralogy of Fallot (TOF) and evaluates the right (RV) and left (LV) ventricular contractility and LV function using speckle-tracking analysis of the endocardium. The study group consisted of 44 fetuses with TOF, of which 34% had pulmonary valve atresia (N=15) and 59% (N=26) had pulmonary valve stenosis. The RV and LV global fractional area change, longitudinal contractility (longitudinal strain, free wall strain, septal strain, free wall and septal annular fractional shortening, and free wall and septal wall annular plane systolic excursion), and transverse contractility (24-segment fractional shortening) as well as LV functional assessment (stroke volume, cardiac output, and ejection fraction) were measured using speckle-tracking analysis. The z-scores of the measurements were compared to 200 controls. Compared to controls, measurements of LV contractility in fetuses with TOF demonstrated significantly abnormal values for global contractility, longitudinal contractility, and transverse contractility of the mid and apical segments. LV function was abnormal for stroke volume (SV), cardiac output (CO), and ejection fraction (EF). In comparison, RV contractility demonstrated no significant difference between TOF and control z-score values for RV global contractility. Only two RV measurements were found to be abnormal: longitudinal contractility and transverse contractility of the apical segments. Using multiple measurement tools to evaluate global, longitudinal, and transverse contractility, this study identified significant differences between fetuses with TOF and healthy controls, with greater contractility abnormalities seen in the LV than in the RV.

Spinal cord injury impairs cardiac function due to impaired bulbospinal sympathetic control

Spinal cord injury chronically alters cardiac structure and function and is associated with increased odds for cardiovascular disease. Here, we investigate the cardiac consequences of spinal cord injury on the acute-to-chronic continuum, and the contribution of altered bulbospinal sympathetic control to the decline in cardiac function following spinal cord injury. By combining experimental rat models of spinal cord injury with prospective clinical studies, we demonstrate that spinal cord injury causes a rapid and sustained reduction in left ventricular contractile function that precedes structural changes. In rodents, we experimentally demonstrate that this decline in left ventricular contractile function following spinal cord injury is underpinned by interrupted bulbospinal sympathetic control. In humans, we find that activation of the sympathetic circuitry below the level of spinal cord injury causes an immediate increase in systolic function. Our findings highlight the importance for early interventions to mitigate the cardiac functional decline following spinal cord injury.

Assessment of Cardiac Function during First Pregnancy Using Speckle Tracking Echocardiography

Background: Pregnancy is a dynamic process associated with significant and thorough hormonal and hemodynamic changes that directly or indirectly influence cardiac function. However, the effect of these alterations on left ventricular myocardial contractile function has not been fully illustrated. Objective: To assess the maternal cardiac function during the third trimester of first pregnancy using Speckle Tracking echocardiography. Results: This cross sectional study was carried out in Baghdad teaching hospital in the time period from November 2020 to June 2021. A total of 100 women were studied, they were classified into two groups: 50 non pregnant women with mean age (24.6 ±4.60 years) served as control group, and 50 pregnant women with normal singleton pregnancy (30-40 weeks of gestation) with mean age (23.6±3.63 year) served as study group. The left ventricular systolic function was assessed using transthoracic echocardiography to measure LV ejection fraction EF%. Furthermore, the left ventricular contractile function evaluated with speckle tracking echocardiography (STE) by measuring LV global longitudinal strain (GLS). The left ventricular ejection fraction shows no significant difference between pregnant and control group (p= 0.214), while the left ventricular global longitudinal strain (GLS) shows significant decrease in the pregnant females in their third trimester (p=0.001). Conclusion: left ventricular global longitudinal strain (GLS) shows significant reduction during the third trimester of normal first pregnancy.

Cardiomyocyte-GSK-3β deficiency induces cardiac progenitor cell proliferation in the ischemic heart through paracrine mechanisms.

Cardiomyopathy is an irreparable loss and novel strategies are needed to induce resident cardiac progenitor cell (CPC) proliferation in situ to enhance the possibility of cardiac regeneration. Here, we sought to identify the potential roles of glycogen synthase kinase-3β (GSK-3β), a critical regulator of cell proliferation and differentiation, in CPC proliferation post-myocardial infarction (MI). Cardiomyocyte-specific conditional GSK-3β knockout (cKO) and littermate control mice were employed and challenged with MI. Though cardiac left ventricular chamber dimension and contractile functions were comparable at 2 weeks post-MI, cKO mice displayed significantly preserved LV chamber and contractile function versus control mice at 4 weeks post-MI. Consistent with protective phenotypes, an increased percentage of c-kit-positive cells (KPCs) were observed in the cKO hearts at 4 and 6 weeks post-MI which was accompanied by increased levels of cardiomyocyte proliferation. Further analysis revealed that the observed increased number of KPCs in the ischemic cKO hearts was mainly from a cardiac lineage, as the majority of identified KPCs were negative for the hematopoietic lineage marker, CD45. Mechanistically, cardiomyocyte-GSK-3β profoundly suppresses the expression and secretion of growth factors, including basic-fibroblast growth factor, angiopoietin-2, erythropoietin, stem cell factor, platelet-derived growth factor-BB, granulocyte colony-stimulating factor, and vascular endothelial growth factor, post-hypoxia. In conclusion, our findings strongly suggest that loss of cardiomyocyte-GSK-3β promotes cardiomyocyte and resident CPC proliferation post-MI. The induction of cardiomyocyte and CPC proliferation in the ischemic cKO hearts is potentially regulated by autocrine and paracrine signaling governed by dysregulated growth factors post-MI. A strategy to inhibit cardiomyocyte-GSK-3β could be helpful for the promotion of in situ cardiac regeneration post-ischemic injury.

Abstract 11402: Targeting RyR2 to Suppress Ventricular Arrhythmias and Improve Left Ventricular Function in Chronic Ischemic Heart Disease

Introduction: Sarcoplasmic reticulum Ca +2 leak from RyR2 is a common finding in chronic ischemic heart disease (CIHD) and may be a key driver for ventricular arrhythmias and reduced excitation-contraction coupling in failingm myocytes. Here, we test the hypothesis that targeting Ca +2 leak using the non-selective RyR inhibitor, Dantrolene, suppresses ventricular arrhythmias and improves left ventricular contractile function in CIDH. Methods: CHID was induced in 24 C57BL/6J mice by left coronary artery ligation. Four weeks after myocardial infarction (MI), subcutaneous osmotic pumps were placed to deliver continuous dantrolene (20 mg/kg/day) or vehicle (0.9% Saline). Left ventricular (LV) function was assessed by echocardiogram at 4-, 7- and 10-weeks post-MI. Peripheral muscle strength was assessed by provoked electromyogram at 6 weeks. Inducibility of ventricular tachycardia (VT) was assessed by rapid transesophageal pacing with isoproterenol at 10 weeks. Results: Dantrolene reduced the peripheral muscle strength in mice (0.014±0.001 vs 0.010±0.001 N, P&lt;0.05), but had no adverse effects on weight loss or mortality. Dantrolene increased fractional shortening (18.7±1.3% vs 22.1±1.6%, P&lt;0.001) and mean velocity fiber shortening (mVcfc 1.37±0.09 vs 1.74±0.1 circ/sec, P&lt;0.002) in non-infarcted regions at 10 weeks. This prevented the progression in LV ejection fraction reduction from 4 to 10 weeks (Saline: 35.6±3.4% to 30.6%±3.4%; Dantrolene 34.6±2.4% to 38.1±1.9% vs, P&lt;0.01). Dantrolene reduced VT frequency per animal (0.083±0.04 vs 0.028±0.02 VT/pacing train, P&lt;0.02) and the total duration of inducible VT per animal (59.2±24 secs vs 1.2±0.6 sec, P&lt;0.04). Dantrolene significantly prolonged the ventricular effective refractory period (VERP) (35.1±1.6 msec vs 42.0±0.9 msec, P&lt;0.005). Conclusion: Dantrolene suppression of RyR2 diastolic Ca +2 leak in chronic ischemic heart failure improves the systolic function of surviving myocardium and reduces VT burden by prolonging the VERP, preventing the re-entry circuit for VT in this model. RyR2 inhibition may represent a new therapeutic target for the treatment of CIDH with ventricular arrhythmias.

Abstract P409: GSK-3β Deficiency In Cardiomyocyte Induces Cardiac Progenitor Cell Proliferation In The Ischemic Heart

The cardiomyocytes are terminally differentiated cells and ischemia-induced cardiomyopathy is an irreparable loss. Novel strategies are needed to induce resident cardiac progenitor cells (CPCs) proliferation in situ to enhance the possibility of cardiac regeneration. Here we sought to identify a potential role for glycogen synthase kinase-3β (GSK-3β), a critical regulator of cell proliferation and differentiation, in CPCs proliferation in the ischemic heart. Cardiomyocyte-specific conditional GSK-3β knockout (cKO) and littermate control mice were recruited and challenged with myocardial infarction (MI). The cardiac function was assessed using trans-thoracic M-mode echocardiography. The level of CPC proliferation in the ischemic cKO hearts was determined at 2, 4 and 8 weeks post-MI through immunofluorescence labeling of stem cell marker c-Kit. To confirm the lineage of identified c-Kit -positive cells (KPCs) in the heart, a hematopoietic lineage marker was stained along with c-Kit. The cardiac left ventricular chamber dimension (LVID) and contractile functions were comparable until 2 weeks post-MI. The cKO mice displayed significantly preserved LV chamber [LVIDd(mm); 5.01±0.67 vs.6.09±0.65, p =0.01] and contractile function [LVEF(%); 31.98±8.52 vs. 18.06±7.11., p =0.01] in comparison to control mice at 4 week post-MI. Consistent with protective phenotypes, an increased percentage of KPC was observed in the cKO hearts at 4 and 6-weeks post-MI which was accompanied by an increased level of cardiomyocyte proliferation. Further analysis revealed that the observed increased number of KPCs in the ischemic cKO hearts were mostly from a cardiac lineage as the majority of identified KPCs were negative for the hematopoietic marker, CD45. In conclusion, our findings strongly suggest that GSK-3β inhibits CPCc proliferation post-ischemia, and loss of GSK-3β in cardiomyocytes promotes resident CPCc proliferation potentially through paracrine mechanisms.

Atrial standstill in the newborn: a case report

Introduction. Persistent atrial standstill is a rare syndrome characterized by absence of mechanical and electrical atrial activity. The article presents a unique case of atrial standstill in the newborn patient with tachyarrhythmia.Brief description. The first manifestation of atrial standstill in the patient was heart failure (HF) manifestations and wide-complex tachycardia according to electrocardiography, which was identified as ventricular tachycardia. At the local outpatient clinic, the child was prescribed with antiarrhythmic therapy (AAT), which decreased heart rate. Three months later, a transesophageal electrophysiological study was carried out in our center in order to determine the arrhythmia origin. A multiform idioventricular rhythm with a heart rate of 46-119 beats per min was diagnosed, atrial pacing spike (A waves) was not recorded. Given bradyarrhythmia, hemodynamic abnormalities on echocardiography (significant atrial enlargement, decreased contractility), the patient, in order to prevent the risk of sudden cardiac death, underwent implantation of single chamber pacemaker in VVIR mode and bipolar ventricular lead. Anticoagulant therapy was prescribed. After 6-month follow-up, relief of HF symptoms and an increase in left ventricular contractile function was noted.Discussion. Timely diagnosis and implantation of pacemakers allowed avoiding AAT and minimizing the HF symptoms. Continuous ventricular pacing and anticoagulant therapy are important in HF prevention.

Assessment of left ventricular contractile function during chemotherapy

Assessment of left ventricular contractile function during chemotherapy

Mechanical Dyssynchrony for Prediction of the Cardiac Resynchronization Therapy Response in Patients with Dilated Cardiomyopathy.

Aim To evaluate the predictive value of indexes of left ventricular mechanical dyssynchrony (MD) as determined by data of electrocardiogram (ECG)-gated myocardial perfusion scintigraphy (ECG-MPS) for prediction of the efficacy of resynchronization therapy (RT) in patients with chronic heart failure (CHF).Material and methods This prospective study included 32 patients with nonischemic CHF and standard indications for RT. All patients underwent complete clinical an instrumental examination, including 24-h ECG monitoring and echocardiography (EchoCG). In order to evaluate the left ventricular (LV) myocardial perfusion, contractile function, and MD, myocardial perfusion scintigraphy was performed for all patients at rest prior to RT. In addition to the perfusion defect size at rest and hemodynamic parameters, LV MD was determined. The following indexes were used for analysis of dyssynchronization: phase standard deviation (PSD), phase histogram bandwidth (HBW), and phase histogram asymmetry and steepness. The treatment efficacy was evaluated by the clinical status of patients (clinical condition evaluation scale for CHF patient) and EchoCG at 6 months following RT. The criteria for a positive response to RT were an increase in LV ejection fraction (EF) by 5% and/or a decrease in the LV end-diastolic volume by 15% compared to preoperative values.Results According to ECG-MPS findings, all patients had scintigraphic signs of severe CHF with dilated LV cavity (end-diastolic volume, EDV 246 [217; 269] ml) and also of pronounced mechanical and electrical dyssynchrony. The values of mechanical dyssynchrony were PSD 53 [41; 61], HBW 176 [136; 202], asymmetry 1.62 [1.21; 1.89], and steepness 2.81 [1.21; 3.49]. The QRS duration was 165 [155; 175] msec. Furthermore, the LV perfusion was moderately impaired (perfusion defect size 4 [3; 10] %). Mean follow-up duration after implantation of the resynchronizing device was 6±1.7 mos. According to the selected criteria, 20 (63 %) patients were considered as responders and 12 (37 %) patients as non-responders. Before implantation of the cardiac synchronizing device, responders and non-responders differed only in LV MD (PSD 44 [35; 54] vs. 63 [58; 72]; p=0.0001); HBW 158 [118; 179] vs. 205 [199; 249]; p=0.0001; asymmetry 1.77 [1.62; 2.02] vs. 1.21 [0.93; 1.31]; p=0.0001; steepness 3.03 [2.60; 3.58] vs. 1.21 [0.19; 1.46]; p=0.0001), respectively. A one-factor logistic regression analysis showed that MD values were statistically significant predictors of a positive response to RT. A multi-factor logistic analysis of phase histogram steepness (odds ratio, OR 1.196; 95 % confidence interval, CI 1.04-1.37) and PSD (OR 0.67; 95 % CI 0.47-0.97) were identified as independent predictors for the response to RT. According to results of the ROC analysis, a PSD &lt;55 and a phase histogram steepness &gt;1.54 may predict the effectiveness of RT (AUC= 0.92; р=0.0001).Conclusion LV MD parameters determined with ECG-MPS allow predicting the effectiveness of RT in patients with nonischemic CHF. In this patient group, high values of standard deviation and low values of phase histogram steepness were independent predictors for the absence of response to RT after 6 mos. of follow-up.

Prospects for the use of thyroid hormones in patients with heart failure

Thyroid hormone therapy in the setting of heart failure is still an «open book» today. There are several unanswered questions: the regimen, doses and schedule of the use of thyroid hormones, the consequences of such therapy. At the same time, the presence of a comorbid pathology of the thyroid gland, which requires the appointment of levothyroxine, allows one to partially answer these questions. Thyroid hormones affect the diastolic and systolic functions of the myocardium. Ventricular contractile function is also affected by changes in hemodynamic conditions secondary to thyroid hormones and peripheral vascular tone. Thyroid hormone homeostasis maintains a positive ventricular-arterial ratio, resulting in a favorable balance for heart function. Experimental studies in rats have shown that chronic hypothyroidism alone can eventually lead to heart failure. Other studies suggest a decrease in the level of free triiodothyronine in the myocardium after myocardial infarction or with arterial hypertension due to the activation of type 3 deiodinase, which leads to deactivation of triiodothyronine and thyroxine. To address these issues, the researchers propose conducting multicenter, randomized, placebo-controlled trials to evaluate the effects of thyroxine replacement in patients with chronic heart failure. The review highlights the growing body of evidence from animal studies and small clinical trials that suggests that low thyroid activity at the cardiac tissue level can negatively affect the progression of heart failure and that treatment with thyroid hormones can lead to an improved prognosis.

Trastuzumab-induced cardiotoxicity: a review of clinical risk factors, pharmacologic prevention, and cardiotoxicity of other HER2-directed therapies.

Despite great success as a targeted breast cancer therapy, trastuzumab use may be complicated by heart failure and loss of left ventricular contractile function. This review summarizes the risk factors, imaging, and prevention of cardiotoxicity associated with trastuzumab and other HER2-targeted therapies. Cardiovascular disease risk factors, advanced age, and previous anthracycline treatment predispose to trastuzumab-induced cardiotoxicity (TIC), with anthracycline exposure being the most significant risk factor. Cardiac biomarkers such as troponins and pro-BNP and imaging assessments such as echocardiogram before and during trastuzumab therapy may help in early identification of TIC. Initiation of beta-adrenergic antagonists and angiotensin converting enzyme inhibitors may prevent TIC. Cardiotoxicity rates of other HER2-targeted treatments, such as pertuzumab, T-DM1, lapatinib, neratinib, tucatinib, trastuzumab deruxtecan, and margetuximab, appear to be significantly lower as reported in the pivotal trials which led to their approval. Risk assessment for TIC should include cardiac imaging assessment and should incorporate prior anthracycline use, the strongest risk factor for TIC. Screening and prediction of cardiotoxicity, referral to a cardio-oncology specialist, and initiation of effective prophylactic therapy may all improve prognosis in patients receiving HER2-directed therapy. Beta blockers and ACE inhibitors appear to mitigate risk of TIC. Anthracycline-free regimens have been proven to be efficacious in early HER2-positive breast cancer and should now be considered the standard of care for early HER2-positive breast cancer. Newer HER2-directed therapies appear to have significantly lower cardiotoxicity compared to trastuzumab, but trials are needed in patients who have experienced TIC and patients with pre-existing cardiac dysfunction.

Endothelial dysfunction in obstructive sleep apnea patients

PurposeObstructive sleep apnea syndrome (OSAS) is an independent risk factor for cardiovascular diseases. The aim of the study was to assess the influence of OSAS on endothelial dysfunction and thrombosis biomarkers and to evaluate the effect of treatment with continuous positive airway pressure (CPAP) on biomarker levels.MethodsNT-proBNP, sICAM-1, endothelin-1, von Willebrand factor, D-dimers, and thrombin-antithrombin complex (TAT) were measured in 50 patients diagnosed with moderate-to-severe OSAS. All patients underwent transthoracic echocardiography, and 38 months after the inclusion, 16 CPAP users and 22 non-CPAP users were reassessed.ResultsSleep-related indices of apnea-hypopnea index (AHI) and mean SpO2 were associated with higher sICAM-1 levels (AHI < 30: 7.3 ± 4.7 vs. AHI ≥ 30: 19.5 ± 19.4 mg/ml, p = 0.04; SpO2 ≥ 90%: 11.9 ± 9.3 vs. SpO2 < 90%: 23.6 ± 25.8, p = 0.04). sICAM-1 levels were significantly higher in obese patients, particularly with BMI ≥ 40. Plasma levels of TAT were significantly correlated with the increased right ventricular size (right ventricular diameter ≤ 37 mm: 0.86 ± 0.70 vs. > 37 mm: 1.96 ± 1.20 ng/ml, p = 0.04). Endothelin-1 levels were higher in patients with decreased right ventricular function (right ventricle TDI-derived S′ ≥ 12 cm/s: 11.5 ± 10.9 vs. < 12 cm/s: 26.0 ± 13.2 pg/ml, p = 0.04). An increase in NT-proBNP was related to impaired parameters of the right ventricular contractile function. There were no correlations between long-term CPAP therapy and the levels of biomarkers.ConclusionSevere OSAS influences endothelial damage as manifested by an increase in sICAM-1 levels. Changes in right ventricular structure and function, observed mainly in patients with higher TAT and endothelin-1 levels, are also manifested by an increase in NT-proBNP levels. Long-term CPAP treatment does not seem to influence biomarkers in patients with moderate-to-severe OSAS, which may help to explain the lack of influence of CPAP on cardiovascular risk reduction.

Prognostic Implication of RV Coupling to Pulmonary Circulation for Successful Weaning From Extracorporeal Membrane Oxygenation

ObjectivesThe aim of this study was to explore if right ventricular (RV) contractile function and its coupling to pulmonary circulation (PC) were associated with successful weaning from venoarterial−extracorporeal membrane oxygenation (VA-ECMO) at maintenance of pump flow. BackgroundLimited data are available on predictors of successful weaning from VA-ECMO. MethodsA total of 79 patients with cardiogenic shock underwent transthoracic echocardiography to evaluate weaning from ECMO and were prospectively enrolled between 2016 and 2019. The noninvasively measured RV-PC coupling index was acquired by indexing tricuspid annular S' velocity, tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), and RV free-wall longitudinal strain (FWLS) to right ventricular systolic pressure (RVSP). ResultsTransthoracic echocardiography was performed at a median 3.0 days (range 1 to 6 days) after ECMO initiation at a median ECMO flow of 3.2 l/min (range 3.0 to 3.6 l/min). The RV-PC coupling matrix, tricuspid annular S'/RVSP, TAPSE/RVSP, and RV FWLS/RVSP exhibited satisfactory predictive performances for predicting successful weaning from ECMO. Using the best cutoff values derived from the area under the receiver-operator characteristic curve, tricuspid annular S'/RVSP demonstrated a significantly better predictive performance than conventional echocardiographic parameters (left ventricular ejection fraction >20%, left ventricular outflow tract time-velocity integral ≥10 cm, and mitral annular S' ≥6 cm/s). ConclusionsEchocardiographic RV-PC coupling metrics exhibited a significantly better performance for predicting successful weaning from VA ECMO compared with conventional echocardiographic criteria at maintenance of pump flow.

Iron Deficiency Is Associated With Impaired Biventricular Reserve and Reduced Exercise Capacity in Patients With Unexplained Dyspnea

BackgroundIron deficiency (ID) is frequent and associated with diminished exercise capacity in heart failure (HF), but its contribution to unexplained dyspnea without a HF diagnosis at rest remains unclear. Methods and ResultsConsecutive patients with unexplained dyspnea and normal echocardiography and pulmonary function tests at rest underwent prospective standardized cardiopulmonary exercise testing with echocardiography in a tertiary care dyspnea clinic. ID was defined as ferritin of <300 µg/L and a transferrin saturation of <20% and its impact on peak oxygen uptake (peakVO2), biventricular response to exercise, and peripheral oxygen extraction was assessed. Of 272 patients who underwent cardiopulmonary exercise testing with echocardiography, 63 (23%) had ID. For a similar respiratory exchange ratio, patients with ID had lower peakVO2 (14.6 ± 7.6 mL/kg/minvs 17.8 ± 8.8 mL/kg/min; P = .009) and maximal workload (89 ± 50 watt vs 108 ± 56 watt P = .047), even after adjustment for the presence of anemia. At rest, patients with ID had a similar left ventricular and right ventricular (RV) contractile function. During exercise, patients with ID had lower cardiac output reserve (P < .05) and depressed RV function by tricuspid s' (P = .004), tricuspid annular plane systolic excursion (P = .034), and RV end-systolic pressure-area ratio (P = .038), with more RV–pulmonary artery uncoupling measured by tricuspid annular plane systolic excursion/systolic pulmonary arterial pressure ratio (P = .023). RV end-systolic pressure-area ratio change from rest to peak exercise, as a load-insensitive metric of RV contractility, was lower in patients with ID (2.09 ± 0.72 mm Hg/cm2 vs 2.58 ± 1.14 mm Hg/cm2; P < .001). ID was associated with impaired peripheral oxygen extraction (peakVO2/peak cardiac output; P = .036). Cardiopulmonary exercise testing with echocardiography resulted in a diagnosis of HF with preserved ejection fraction in 71 patients (26%) based on an exercise E/e' ratio of >14, with equal distribution in patients with (28.6%) or without ID (25.4%, P = .611). None of these findings were influenced in a sensitivity analysis adjusted for a final diagnosis of HFpEF as etiology for the unexplained dyspnea. ConclusionsIn patients with unexplained dyspnea without clear HF at rest, ID is common and associated with decreased exercise capacity, diminished biventricular contractile reserve, and decreased peripheral oxygen extraction.

Left ventricular myocardial strain quantification with two- and three-dimensional cardiovascular magnetic resonance based tissue tracking.

Cardiovascular magnetic resonance based tissue tracking (CMR-TT) was reported to provide detailed insight into left ventricular (LV) contractile function and deformation with both of two- and three-dimensional (2/3D) algorithms. This study was designed to investigate the feasibility and reproducibility of these two techniques for measuring LV global and segmental strain, and establish gender- and age-related reference values of global multi-dimensional peak strains among large healthy population. We retrospectively recruited 150 healthy volunteers (75 males/females) and divided them into three age groups (G20-40, G41-60 and G61-80). LV global mean and peak strains as well as segmental strains in radial, circumferential and longitudinal directions were derived from post-hoc 2/3D CMR-TT analysis of standard steady-state free precession (SSFP) cine images acquired at 1.5T field strength. Both 2D and 3D CMR-TT modalities enable the tracking of LV myocardial tissues and generate global and segmental strain data. By comparison, 3D CMR-TT was more feasible in measuring segmental deformation since it could generate values at all segments. The amplitudes of LV 3D global peak strain were the smallest among those of 2/3D corresponding global mean or peak strains except in the radial direction, and was highly correlated with 2D global mean strains (correlation coefficient r=0.71-0.90), 2D global peak strains (r=0.75-0.89) and 3D global mean strains (all r=0.99). In healthy cohort, LV 3D global peak values were 44.4%±13.0% for radial, -17.0%±2.7% for circumferential and -15.4%±2.3% for longitudinal strain. Females showed significantly larger amplitude of strains than males, especially in G61-80 (P<0.05). The subjects in G61-80 showed larger amplitude of strains than the volunteers in younger groups. The intra- and inter-observer agreement of 2/3D CMR-TT analysis in evaluating LV myocardial global deformation was better than segmental measurement. CMR-TT is a feasible and reproducible technique for assessing LV myocardial deformation, especially at the global level. The establishment of specific reference values of LV global and segmental systolic strains and the investigation of dimension-, gender- and age-related differences provide a fundamental insight into the features of LV contraction and works as an essential step in clinical routine.

Fat-1 transgenic mice rich in endogenous omega-3 fatty acids are protected from lipopolysaccharide-induced cardiac dysfunction.

AimsCardiac malfunctions developing in result of sepsis are hard to treat so they eventually contribute to the increased mortality. Previous reports indicated for therapeutic potential of exogenous ω‐3 polyunsaturated fatty acids (PUFA) in sepsis, but potential benefits of this compound on the malfunctional heart have not been explored yet. In the present study, we investigated whether the constantly elevated levels of endogenous ω‐3 PUFA in transgenic fat‐1 mice would alleviate the lipopolysaccharide (LPS)‐induced cardiac failure and death.Methods and resultsAfter both wild type (WT) and transgenic fat‐1 mice were challenged with LPS, a Kaplan–Meier curve and echocardiography were performed to evaluate the survival rates and cardiac function. Proteomics analysis, RT‐PCR, western blotting, immune‐histochemistry, and transmission electron microscopy were further performed to investigate the underlying mechanisms. Results showed that transgenic fat‐1 mice exhibited the significantly lower mortality after LPS challenge as compared with their WT counterparts (30% vs. 42.5%, P < 0.05). LPS injection consistently impaired the left ventricular contractile function and caused the cardiac injury in the wild type mice, but not significantly affected the fat‐1 mice (P < 0.05). Proteomic analyses, ELISA, and immunohistochemistry further revealed that myocardium of the LPS‐challenged fat‐1 mice demonstrated the significantly lower levels of pro‐inflammatory markers and ROS than WT mice. Meaningfully, the LPS‐treated fat‐1 mice also demonstrated a significantly higher levels of LC3 II/I and Atg7 expressions than the LPS‐treated WT mice (P < 0.05), as well as displayed a selectively increased levels of peroxisome proliferator‐activated receptor (PPAR) γ and sirtuin (Sirt)‐1 expression, associated with a parallel decrease in NFκB activation.ConclusionsThe fat‐1 mice were protected from the detrimental LPS‐induced inflammation and oxidative stress, and exhibited enhancement of the autophagic flux activities, associating with the increased Sirt‐1 and PPARγ signals.

Positive Inotropic Effects of ATP Released via the Maxi-Anion Channel in Langendorff-Perfused Mouse Hearts Subjected to Ischemia-Reperfusion.

The organic anion transporter SLCO2A1 constitutes an essential core component of the ATP-conductive large-conductance anion (Maxi-Cl) channel. Our previous experiments using Langendorff-perfused mouse hearts showed that the Maxi-Cl channel contributes largely to the release of ATP into the coronary effluent observed during 10-min reperfusion following a short period (6 min) of oxygen-glucose deprivation. The present study examined the effect of endogenous ATP released via Maxi-Cl channels on the left ventricular contractile function of Langendorff-perfused mouse hearts, using a fluid-filled balloon connected to a pressure transducer. After the initial 30-min stabilization period, the heart was then perfused with oxygen-glucose-deprived Tyrode solution for 6 min, which was followed by a 10-min perfusion with oxygenated normal Tyrode solution in the absence and presence of an ATP-hydrolyzing enzyme, apyrase, and/or an adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). In the absence of apyrase and DPCPX, the left ventricular developed pressure (LVDP) decreased from a baseline value of 72.3 ± 7.1 to 57.5 ± 5.5 mmHg (n = 4) at the end of 6-min perfusion with oxygen-glucose-deprived Tyrode solution, which was followed by a transient increase to 108.5 ± 16.5 mmHg during subsequent perfusion with oxygenated normal Tyrode solution. However, in the presence of apyrase and DPCPX, the LVDP decreased to the same degree during 6-min perfusion with oxygen-glucose-deprived Tyrode solution, but failed to exhibit a transient increase during a subsequent perfusion with oxygenated normal Tyrode solution. These results strongly suggest that endogenous ATP released through Maxi-Cl channels contributes to the development of transient positive inotropy observed during reperfusion after short-period hypoxia/ischemia in the heart.

The Effects of Amino Acids Enriched Del Nido Cardioplegia on Myocardial Leucocyte Accumulation and Ventricular Functions in Patients Undergoing Coronary Artery Bypass Grafting Surgery.

One of the main sources of ischemia/reperfusion injury (IRI) and release of free oxygen radicals (FORs) during extracorporeal circulation (ECC) during cardiac surgery is neutrophils. In this study, we investigated the potential effects of our modification of del Nido cardioplegia (mDNC) (amino acids enriched del Nido cardioplegia) on myocardial polymorphonuclear leucocyte (PMNL) accumulation. We also compared the effects of our mDND and classical del Nido cardiplegia (cDNC) on ventricular contractile functions in coronary artery bypass grafting (CABG) surgery. Our study included 100 isolated CABG patients with similar characteristics, including age, gender, preoperative medications, diabetes, hypertension, and left ventricular ejection fraction (LVEF). The patients were divided into two groups. Amino acids supplemented del Nido cardioplegia (L-aspartate and L-glutamate at a dose of 13 milimol/L) in 50 patients (study group, G1). In the remaining 50 patients, we used a classical del Nido cardioplegic solution (cDNC) (control group, G2). Myocardial Tru-Cut biopsy from the right ventricle was taken before the institution of ECC and after weaning from ECC in all patients. Cardiac troponine-I (cTn-I), tumor necrosis factor-alpha (TNF-Alpha), Pro-Brain Natriuretic Peptide (Pro-BNP), and lactate levels were measured pre- and postoperatively. Invasive monitoring was performed to provide the left ventricular functions in both groups in the operating room and noted by a blinded anaesthesiologist. Five patients died post-surgery (5%) (two from SG and three from CG (P = .67), due to low cardiac output syndrome or multiorgan failure. At the postoperative period, cardiac output (CO) and stroke volume index (SVI) was higher in mDNC (mean ± SDS; 32.1 ± 7 versus 22.2 ± 6.9 mL/min/m² (P < .001). CI was significantly higher in mDNC after surgery (3.10 ± 0.76 versus 2.40 ± 0.30L/min/m² (P = .002). Ten patients (20%) in mDNC and 16 patients (32%) in cDNC required inotropic support (P < .001). The postoperative inotropic requirement was less in mDNC (6.1 ± 1.8 mg/kg versus 9.2 ± 1.9 mg/kg, P < .004). Blood gas analyses from the coronary sinus showed that myocardial acidosis was more severe in the control group [pH (0.10 ± 0.09 versus 0.054 ± 0.001; P = .34)]. Blood lactate levels were significantly high in the control group (1.01 ± 0.007 mmol/L versus 1.92 ± 0.35 mmol/L) (P = .22). No difference was found when compared with cardioplegia volume in the mDNC and cDNC groups (mDNC= 990.00 ± 385 mL in DNC = 960 ± 240 mL, P = .070). An aortic cross-clamp time in the mDNC and cDNC groups were 88.4 ± 8.9 min, and 93 ± 11 min, (P = .76), but cardiopulmonary bypass time was significantly low in mDNC (mDNC = 98.3 ± 22.5 min, DNC = 126 ± 19.5 min, P = .0020). TNF-Alpha and Pro-BNP levels in patients received mDNC were significantly low (P = .022). Postoperative cardiac enzyme levels (creatine kinase-MB and high sensitive troponin-I) were significantly low in the mDNC group (P = .0034). Myocardial biopsy results showed that myocardial PMNL accumulation was significantly high in the control group (P = .001). The amount of inotropic agent use was significantly high in the control group (P = .003). After weaning from ECC, the left ventricular stroke work index (LVSWI), cardiac index (CI), and heart rate (HR) were significantly high in the study group (P = .032; P = .002; P = .01). Postoperative blood and blood products requirements were significantly low in the mDNC group (P = .002). At pre-discharge echocardiography, the mDNC group demonstrated significantly higher ventricular ejection fraction (37.9 ± 4.3% and 29.7 ± 3.8%, respectively (P = .003). Our study findings show that glutamate-aspartate supplemented del Nido cardioplegia significantly decrease myocardial PMNL accumulation with reduced release of biochemical markers, including cardiac troponin-I, TNF-alpha, and Pro-Bnp. Our study results demonstrated that amino acids supplementation in del Nido cardioplegia has some advantages in CABG patients, including the decrease of perioperative myocardial infarction and increase significantly the left ventricular functions including ventricular SVI and CI.