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OBJECTIVES This study was conducted to measure suture tie-down forces and evaluate cyclic contractile forces (CCFs) in beating hearts after undersized 3-dimensional (3D) rigid-ring tricuspid valve annuloplasty (TAP). METHODS Eight force transducers were attached to the 3D rigid TAP ring. Segments 1 to 8 were attached from the mid-septal to anterior-septal commissural area in a counterclockwise order. Two-sizes-down ring TAPs were performed in 6 sheep. Tie-down forces and CCF were recorded and analysed at the 8 annular segments and at 3 levels of peak right ventricular pressure (RVP: 30, 50 and 70 mmHg). RESULTS The overall average tie-down forces and CCF were 4.34 ± 2.26 newtons (N) and 0.23 ± 0.09 N, respectively. The CCF at an RVP of 30 mmHg were higher at 3 commissural areas (segments 3, 5 and 8) than at the other segments. The increases in the CCF following changes in the RVP were statistically significant only at the 3 commissural areas (P = 0.012). However, mean CCFs remained low at all annular positions (ranges of average CCF = 0.06–0.46 N). CONCLUSIONS The risk of suture dehiscence after down-sized 3D rigid-ring TAP might be minimal because the absolute forces remained low in all annular positions even in the condition of high RVP. However, careful suturing in the septal annular area and commissures is necessary to prevent an annular tear during a down-sized 3D rigid-ring TAP.

BACKGROUND Borderline small ventricular size or technical issues precluding the use of both ventricles may lead to single ventricle palliation. Fontan complications have led some centers to look for alternatives to the traditional pathway. The objective of this study is to evaluate the essential philosophy and outcomes of a new biventricular (BiV) conversion program. METHODS The prospectively collected Children's Memorial Hermann Heart Institute Society of Thoracic Surgeon's Database was retrospectively reviewed between July 2017 and July 2020. RESULTS Thirteen patients met inclusion criteria and underwent BiV conversion during that time. The most frequent diagnosis was malposed great arteries and a ventricular septal defect (VSD) in 4 (31%) patients. Seven (54%) patients were in the first interstage, and 1 (8%) patient had already undergone a Fontan operation before their BiV conversion operation. One or more risk factors for single ventricle palliation (genetic syndrome ≥ moderate atrioventricular valve regurgitation ≥ moderate ventricular dysfunction, presence of signs of Fontan failure) were present in 3 (23%) patients. The median left ventricular end diastolic pressure increased from 5.5 mmHg (4-10 mmHg) to 10 mmHg (6-20 mmHg) postoperatively (p

Calcium dysregulation and mitochondrial dysfunction are key elements in the development of sepsis-induced cardiac dysfunction. Evidences have suggested that inhibition of Wnt/β-Catenin signalling prevents cardiac dysfunction and remodelling in surgical, hypertension and pressure overload models. The present study investigated the effects of Wnt/β-Catenin inhibitor on calcium overload and mitochondrial dysfunction in rat sepsis model of cardiomyopathy. Induction of sepsis by cecal ligation puncture (CLP) resulted in the up-regulation of cardiac β-catenin transcriptional levels and cardiac dysfunction depicted by increased serum lactate dehydrogenase, CK-MB levels reduced maximum (dp/dt max.) and minimum developed pressure (dp/dt min.), increased LVEsDP and relaxation constant tau values. Moreover, oxidative and inflammatory stress, immune cell infiltration, increased myeloperoxidase activity, enhanced caspase-3 activity and fibronectin protein levels were observed in septic rat's heart. Also, septic rat's heart displayed mitochondrial dysfunction due to mPTP opening, increased calcium up-regulation in left ventricular apex tissues and whole heart, increased collagen staining, necrosis and structural damage. Pre-treatment with Wnt/β-Catenin antagonist attenuated sepsis-induced serum and tissue biochemical changes, cardiac dysfunction and structural alterations by inhibiting mitochondrial mPTP opening and restricting calcium overloading in cardiac tissue.

Objective Galectin-10 (Gal-10) is a key molecule involved in eosinophil-mediated suppression of T-cell immune response. Systemic sclerosis (SSc) is characterized by T helper (Th) 2/Th17 immune response and impaired function of regulatory T cells, but the pathological role of Gal-10 has not been studied so far. Therefore, we investigated the clinical correlation of serum Gal-10 levels in SSc patients. Methods Serum Gal-10 levels were determined by enzyme-linked immunosorbent assay in 38 patients with diffuse cutaneous SSc (dcSSc), 30 with limited cutaneous SSc and 20 healthy controls. Clinical correlations of serum Gal-10 levels were examined. Results Serum Gal-10 levels were significantly lower in SSc patients than in healthy controls, especially in dcSSc patients, and inversely correlated with skin score, the percentage of predicted diffusion lung capacity for carbon monoxide and estimated right ventricular systolic pressure (RVSP). Furthermore, serum Gal-10 levels had negative correlations with leucocyte counts and inflammatory parameters. Multivariate regression analysis identified C-reactive protein and RVSP as explanatory parameters for serum Gal-10 levels. Conclusion Decreased serum Gal-10 levels may reflect the impairment of eosinophil-mediated regulatory system for T-cell immune response in SSc, possibly contributing to pulmonary vascular involvement leading to pulmonary arterial hypertension.

Introduction:Systemic ventricular end-diastolic pressure is important in patients with single ventricle heart disease. Predictors of an elevated systemic ventricular end-diastolic pressure prior to bidirectional Glenn operation have been incompletely identified.Methods:All patients who underwent bidirectional Glenn operation operation at our centre between January 2007 and March 2017 were retrospectively identified and patient variables were extracted. For patients who had undergone Fontan operation at the time of this study, post-Fontan patient variables were also extracted.Results:One-hundred patients were included with a median age at pre-bidirectional Glenn operation catheterisation of 4.5 months. In total, 71 (71%) patients had a systemic right ventricle. At the pre-bidirectional Glenn operation catheterisation, the mean systemic ventricular end-diastolic pressure was higher amongst those with systemic right ventricle compared to left ventricle (9.1 mmHg ± 2.1 versus 7.7 ± 2.7 mmHg, p < 0.01). On univariate analysis, pre-bidirectional Glenn operation systemic ventricular end-diastolic pressure was positively associated with the presence of a systemic right ventricle (p < 0.01), history of recoarctation (p = 0.03), history of Norwood operation (p = 0.04), and ventricular systolic pressure (p < 0.01). On multivariate analysis, systemic ventricular end-diastolic pressure was positively associated with the presence of a systemic right ventricle (p < 0.01) and ventricular systolic pressure (p < 0.01). Amongst those who had undergone Fontan operation at the time of study (n = 49), those with a higher pre-bidirectional Glenn operation systemic ventricular end-diastolic pressure were more likely to have experienced death, transplantation, or listed for transplantation (p = 0.02) and more likely to have had heart failure symptoms (p = 0.04) at a mean time from Fontan of 5.2 years ± 1.3.Conclusions:In patients undergoing bidirectional Glenn operation operation, the volume-loaded, pre-bidirectional Glenn operation state may expose diastolic dysfunction that has prognostic value.

Introduction of vector flow mapping (VFM) based on the combination of color Doppler and speckle-tracking echocardiography provides noninvasive assessment of early diastolic intra-ventricular pressure gradient (ED-IVPG). The purpose of this study was to evaluate the value of peak ED-IVPG measurement just after aortic valve closure using VFM for noninvasive estimation of impaired LV untwisting velocity as the index of LV relaxation in the clinical setting. The study included 65 consecutive patients in whom echocardiography was performed for the assessment of LV function. We assessed peak ED-IVPG between LV apex and base by VFM analysis software. We also measured peak LV untwisting velocity and LV twisting by speckle-tracking strain analysis. Peak ED-IVPG was successfully and quickly assessed in all the study patients. Peak ED-IVPG was significantly reduced in patients with impaired peak LV untwisting velocity (

Background and Objective: All three isoforms of nitric oxide (NO) synthase (NOS) are targets for thyroid hormones in the cardiovascular system. The aim of this study was to assess the effects of hypo- and hyperthyroidism on inducible (iNOS), endothelial (eNOS), and neural (nNOS) NOS levels in aorta and heart tissues of male rats. Methods: Rats were divided into control, hypothyroid, and hyperthyroid groups; hypo- and hyperthyroidism were induced by adding propylthiouracil (500 mg/L) and L-thyroxine (12 mg/L) to drinking water for a period of 21 days. On day 21, systolic blood pressure, heart rate, left ventricular developed pressure (LVDP), peak rate of positive and negative (±dp/dt) changes in left ventricular pressure as well as NO metabolites (NOx) and iNOS, eNOS, and nNOS protein levels in aorta and heart, were all measured. Results: Compared to controls, LVDP and ±dp/dt were lower in both hypo- and hyperthyroid rats. Compared to controls, heart rate and systolic blood pressure were lower in hypothyroid and higher in hyperthyroid rats. NOx levels in the heart of hypothyroid rats were lower (53%), whereas that in hyperthyroid rats were higher (56% and 40%) than controls. Compared to controls, hypothyroid rats had lower levels of eNOS, iNOS, and nNOS in the aorta (16%, 34%, and 15%, respectively) and lower iNOS and higher nNOS in heart tissue (27% and 46%). In hyperthyroid rats, eNOS levels were lower (54% and 30%) and iNOS were higher (63%, and 35%) in the aorta and heart while nNOS was lower in the aorta (18%). Conclusion: Hypothyroidism increased while hyperthyroidism decreased the ratio of eNOS/iNOS in aorta and heart; these changes of NOS levels were associated with impaired cardiovascular function.

Mechanical dyssynchrony (MD) affects left ventricular (LV) mechanics and coronary perfusion. To understand the multifactorial effects of MD, we developed a computational model that bidirectionally couples the systemic circulation with the LV and coronary perfusion with flow regulation. In the model, coronary flow in the left anterior descending (LAD) and left circumflex (LCX) arteries affects the corresponding regional contractility based on a prescribed linear LV contractility-coronary flow relationship. The model is calibrated with experimental measurements of LV pressure and volume, as well as LAD and LCX flow rate waveforms acquired under regulated and fully dilated conditions from a swine under right atrial (RA) pacing. The calibrated model is applied to simulate MD. The model can simultaneously reproduce the reduction in mean LV pressure (39.3%), regulated flow (LAD: 7.9%; LCX: 1.9%), LAD passive flow (21.6%), and increase in LCX passive flow (15.9%). These changes are associated with right ventricular pacing compared with RA pacing measured in the same swine only when LV contractility is affected by flow alterations with a slope of 1.4 mmHg/mL(2) in a contractility-flow relationship. In sensitivity analyses, the model predicts that coronary flow reserve (CFR) decreases and increases in the LAD and LCX with increasing delay in LV free wall contraction. These findings suggest that asynchronous activation associated with MD impacts 1) the loading conditions that further affect the coronary flow, which may explain some of the changes in CFR, and 2) the coronary flow that reduces global contractility, which contributes to the reduction in LV pressure. NEW & NOTEWORTHY A computational model that couples the systemic circulation of the left ventricular (LV) and coronary perfusion with flow regulation is developed to study the effects of mechanical dyssynchrony. The delayed contraction in the LV free wall with respect to the septum has a significant effect on LV function and coronary flow reserve.

Objective: Effective mechanical circulatory support (MCS) relies on cardiac function measures to guide titration. Left ventricular end diastolic pressure (LVEDP) is a useful measure that is indirectly estimated using pulmonary artery catheters (PACs). PACs require additional intervention and provide intermittent and unreliable estimations. MCS device signals can estimate LVEDP but are prone to inter-device variability and require rigorous specialized characterization. We present a scalable and implementable approach to calculate LVEDP continuously using device signals. Methods: LVEDP was calculated from MCS device measured aortic pressure and motor current, which approximates the pressure head between the aorta and left ventricle. This motor current-pressure head relationship is device-specific but approximated using existing flow calibration and assumed physiologic relationships. Performance was evaluated with comparison from direct measurement of LVEDP in a series of acute animal models. Results: LVEDP measures ( n = 178,279) from 18 animals had good correlation ( r = 0.84) and calibration (Bland-Altman limits of agreement −7.77 to 7.63 mmHg; mean bias −0.07 ± 0.02 mmHg). The total mean error prediction interval was −3.42 to 3.32 mmHg and RMS error was 3.85 mmHg. Conclusion: LVEDP can be continuously calculated using device signals without specialized characterization. Calculated LVEDP values improved upon PAC estimations and were found using a scalable and manufacturer-accessible method. Significance: This method improves upon existing LVEDP measures without the need for rigorous characterization, external calibration, or additional intervention; this allows widescale deployment of continuous LVEDP measurement for patients on MCS and demonstrates key considerations necessary to translate research-grade technologies.

Pulmonary arterial hypertension (PAH) is a fatal disease whose molecular mechanism is unknown. The trimethylation of lysine 36 on histone 3 (H3K36me3) catalyzed by SETD2 and the modification of N6-methyladenine (m6A) mRNA mediated by METTL14 play important roles in a variety of normal and pathological biological processes. However, the role of these epigenetic controls in the pathogenesis of PAH remains unclear. In this study, the expression of SETD2 and METTL14 was elevated in pulmonary artery smooth muscle cells (PASMCs) of hypoxia-induced PAH mice. We further constructed a mouse model with SETD2 specific knockout in smooth muscle cells (SETD2SM22α Cre). Our results suggest that the lack of SETD2 in SMCs protected mice from hypoxia-induced PAH and significantly reduced right ventricular systolic pressure (RVSP), right ventricular/left ventricular plus septum [RV/(LV+S)] weight ratio, and pulmonary median width. In addition, the absence of SETD2 in SMCs alleviates the level of METTL14 expression and the m6A RNA methylation level in PAH SMCs. These results obtained from mice suggest that strategies that target the inhibition of SETD2/METTL14 activity may be a viable treatment for PAH in a clinical setting.

Backgrounds Assessment of left ventricular filling pressure (LVFP) is of clinical importance in patients with ST elevation myocardial infarction (STEMI). Although several echocardiographic parameters are recommended for the assessment of LVFP, validation of these parameters in patients with STEMI is missing. We aimed to investigate the clinical utility of these parameters in acute settings. Methods: We prospectively included consecutive patients with STEMI. LV end-diastolic pressure (LVEDP) was measured following primary PCI and echocardiographic examination was performed within 24 hours. Mean left atrial pressure (mLAP) was calculated both invasively using Yamamoto’s formula and non-invasively using Naugeh’s formula. Mean LAP was considered increased when exceeded 18 mmHg. Results: Patients were grouped according to LVEDP, group 1(41 patients) and group 2(114 patients).There was no significant difference between groups in terms of comorbidities. NT pro-BNP levels (p

Pulmonary arterial hypertension (PAH) is considered to be a rare progressive disease resulting from restricted flow through the pulmonary arterial circulation resulting ultimately in right-sided heart failure. Most patients with PAH suffer from sleep disorders, reduced aerobic fitness, and mortality risk despite optimized medical treatment. This study investigated the effect of 12 weeks of aerobic training on sleep quality, sleep efficiency, right ventricular systolic pressure (RVSP), and aerobic fitness in patients with PAH. Thirty patients with PAH were randomized to two equal groups, training group (A) and control group (B). The Pittsburg sleep quality index (PSQI) questionnaire and a wrist-worn actigraph were used for the assessment of sleep quality and sleep efficiency respectively. RVSP was measured using echocardiography. Cardiopulmonary exercise testing (CPET) assessed maximal heart rate and VO2max. All were measured before and after the study period for both groups. Exercise training was conducted on a bicycle ergometer as an individually-tailored moderate-intensity aerobic training session (60 to 70% of the maximal heart rate reached during the initial exercise test) for 30 to 45 min/day, 3 sessions/week for 12 weeks (36 sessions). Sleep scores and RVSP showed significant reductions and VO2max—representing the aerobic fitness—showed a significant increase in the group (A) compared with group (B). These results suggest that aerobic training has a positive effect on three risk factors for mortality in patients with PAH, namely sleep quality, decline in exercise capacity, and right ventricular remodeling. Clinical trial registered in ClinicalTrials.gov , ID: NCT04337671.

Background We investigated the feasibility of the clinical application of non‐invasive transthoracic echocardiography for diagnosis of pulmonary arterial hypertension induced by dasatinib (D‐PAH) in chronic myeloid leukemia (CML). Methods A total of 451 CML patients who were examined by 2D‐echocardiography at least once at baseline and/or during dasatinib therapy as frontline (n = 196) and subsequent line (n = 255) therapies were included in this study. D‐PAH was defined as right ventricular systolic pressure (RVSP) >40 mm Hg with relevant symptoms and the absence of other specific etiologies. Results A total of 847 echocardiographies were performed including at baseline (n = 255) and during dasatinib treatment (n = 592). During the median of 36.2 (0.1–181.8) months of dasatinib therapy, the level of RVSP gradually increased (Spearman's r = 0.2819, p 40 mm Hg without (asymptomatic, n = 27, 48.2%) or with symptoms (D‐PAH, n = 29, 51.8%). All asymptomatic patients maintained dasatinib therapy without further symptoms and the D‐PAH patients ultimately switched to other tyrosine kinase inhibitors. After dasatinib discontinuation, 13 (45%) and 15 (52%) patients showed RVSP normalization and gradual decrease, respectively. Conclusions Our large cohort study demonstrated that the gradual increment of RVSP might be induced by dasatinib and non‐invasive echocardiography can be fast way for early diagnosis as well as for monitoring of D‐PAH., (a) The aim of this study was to investigate the fidelity of 2D‐echocardiography for diagnosis of pulmonary arterial hypertension induced by dasatinib (D‐PAH) in chronic myeloid leukemia. (b) The gradual increment of right ventricular systolic pressure might be induced by dasatinib and non‐invasive echocardiography can be fast way for early diagnosis as well as for monitoring of D‐PAH.

Little is known about the sequelae of chronic sympathetic nervous system (SNS) activation in patients with pulmonary arterial hypertension (PAH) and right heart failure (RHF). We aimed to, (1) validate the use of [11C]-meta-hydroxyephedrine (HED) for assessing right ventricular (RV) SNS integrity, and (2) determine the effects of β-receptor blockade on ventricular function and myocardial SNS activity in a PAH rat model. PAH was induced in male Sprague-Dawley rats (N = 36) using the Sugen+chronic hypoxia model. At week 5 post-injection, PAH rats were randomized to carvedilol (15 mg·kg−1·day−1 oral; N = 16) or vehicle (N = 16) for 4 weeks. Myocardial SNS function was assessed with HED positron emission tomography(PET). With increasing PAH disease severity, immunohistochemistry confirmed selective sympathetic denervation within the RV and sparing of parasympathetic nerves. These findings were confirmed on PET with a significant negative relationship between HED volume of distribution(DV) and right ventricular systolic pressure (RVSP) in the RV (r = −0.90, p = 0.0003). Carvedilol did not reduce hemodynamic severity compared to vehicle. RV ejection fraction (EF) was lower in both PAH groups compared to control (p

Background: Currently, patients with COPD who are evaluated for bronchoscopic treatments are routinely screened for pulmonary hypertension (PH) and systolic left ventricle dysfunction by echocardiography. Objectives: We evaluated the prevalence of PH and systolic left ventricle dysfunction in this patient group and investigated if the previously proposed CT-derived pulmonary artery to aorta (PA:A) ratio >1 and PA diameter measurements can be used as alternative screening tools for PH. Methods: Two hundred fifty-five patients were included in this retrospective analysis (FEV1 25%pred, RV 237%pred). All patients received transthoracic echocardiography and chest CT scans on which diameters of the aorta and pulmonary artery were measured at the bifurcation and proximal to the bifurcation. Results: Following echocardiography, 3 patients (1.2%) had PH and 1 (0.4%) had systolic left ventricle dysfunction. Using a PA:A ratio >1, only 10.3% of the patients with a right ventricular systolic pressure (RVSP) ≥35 mm Hg were detected and none of the patients with an RVSP >50 mm Hg were detected. Patients with an RVSP ≥35 mm Hg had significantly higher PA diameters (29.5 vs. 27.5 mm; p = 0.02) but no significantly different PA:A ratios. All patients with an RVSP >50 mm Hg had PA diameters >30 mm. Conclusions: The prevalence of PH and systolic left ventricle dysfunction is low in this preselected cohort of patients with severe COPD. In this population, a PA:A ratio >1 is not a useful cardiac screening tool for PH. A PA diameter >30 mm could substitute for routinely performed echocardiography in the screening for PH in this patient group.

This study explored the clinical meaning of miR-378a-3p in sepsis and its influence on sepsis-induced inflammation and cardiac dysfunction. Serum levels of miR-378a-3p were detected by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). The Receiver Operating Characteristic (ROC) curve was used to evaluate its diagnostic value. The effects of miR-378a-3p on inflammation and cardiac function were evaluated by monitoring left ventricular systolic pressure (LVSP), left ventricular and end-diastolic pressure (LVEDP), maximum rate of change in left ventricular pressure (± dp/dtmax) and detecting the levels of troponin I (cTnI), creatine kinase isoenzyme MB (CK-MB), tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), and interleukin-1β (IL-1β) via enzyme linked immunosorbent assay (ELISA). Serum miR-378a-3p was increased in sepsis patients and rat model. ROC curve indicated that miR-378a-3p might have diagnostic significance for sepsis miR-378a-3p antagomir improved the cardiac function by upregulating the levels of LVSP and ± dp/dtmax, and decreasing the levels of LVEDP, cTnI and CK-MB in rat model. miR-378a-3p antagomir also significantly alleviated the inflammatory responseby down-regulating the expression of TNF-a, IL-6, and IL-1β. Besides, logistics regression analysis illustrated that miR-378a-3p was an independent influencing factor for the onset of cardiac dysfunction in sepsis. miR-378a-3p has the potential as a diagnostic biomarker for sepsis and decreasing the level of miR-378a-3p had the ability to ameliorate cardiac dysfunction and inflammatory response caused by sepsis.

Heart failure (HF) post-myocardial infarction (MI) presents with increased vulnerability to monomorphic ventricular tachycardia (mmVT). To appropriately evaluate new therapies for infarct-mediated reentrant arrhythmia in the preclinical setting, chronologic characterization of the preclinical animal model pathophysiology is critical. This study aimed to evaluate the rigor and reproducibility of mmVT incidence in a rodent model of HF. We hypothesize a progressive increase in the incidence of mmVT as the duration of HF increases. Adult male Sprague-Dawley rats underwent permanent left coronary artery ligation or SHAM surgery and were maintained for either 6 or 10 wk. At end point, SHAM and HF rats underwent echocardiographic and invasive hemodynamic evaluation. Finally, rats underwent electrophysiologic (EP) assessment to assess susceptibility to mmVT and define ventricular effective refractory period (ERP). In 6-wk HF rats (n = 20), left ventricular (LV) ejection fraction (EF) decreased (P < 0.05) and LV end-diastolic pressure (EDP) increased (P < 0.05) compared with SHAM (n = 10). Ten-week HF (n = 12) revealed maintenance of LVEF and LVEDP (P > 0.05), (P > 0.05). Electrophysiology studies revealed an increase in incidence of mmVT between SHAM and 6-wk HF (P = 0.0016) and ERP prolongation (P = 0.0186). The incidence of mmVT and ventricular ERP did not differ between 6- and 10-wk HF (P = 1.0000), (P = 0.9831). Findings from this rodent model of HF suggest that once the ischemia-mediated infarct stabilizes, proarrhythmic deterioration ceases. Within the 6- and 10-wk period post-MI, no echocardiographic, invasive hemodynamic, or electrophysiologic changes were observed, suggesting stable HF. This is the necessary context for the evaluation of experimental therapies in rodent HF. NEW & NOTEWORTHY Rodent model of ischemic cardiomyopathy exhibits a plateau of inducible monomorphic ventricular tachycardia incidence between 6 and 10 wk postinfarction.

Context: Left ventricular end-diastolic pressure (LVEDP) reportedly increases after left ventriculography (LVG), and patients with congestive heart failure (CHF) tend to have high LVEDP. We hypothesized that increased LVEDP after LVG is directly associated with hospitalization for CHF. Aims: This study aims to investigate whether a predictive association exists between increased LVEDP after LVG and CHF-related hospitalization. Settings and Design: This was retrospective, single-center (hospital), observational study. Subjects and Methods: We analyzed data of 68 consecutive patients who underwent LVG between March 2015 and July 2017. Patients were divided into the following two groups: those with ΔLVEDP ≥6 mmHg during LVG and those with ΔLVEDP

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease that is characterized by the irreversible remodeling of the pulmonary artery. Although several PAH drugs have been developed, additional drugs are needed. Rho kinases (ROCKs) are involved in the pathogenesis of PAH, and thus, their inhibitors may prevent the development of PAH. However, the therapeutic benefits of ROCK isoform-specific inhibitors for PAH remain largely unknown. The in vitro and in vivo effects of the ROCK2-specific inhibitor, KD025, were examined herein using pulmonary arterial smooth muscle cells (PASMCs) from idiopathic pulmonary arterial hypertension (IPAH) patients and monocrotaline (MCT)-induced pulmonary hypertensive (PH) rats. The expression of ROCK1 was similar between normal- and IPAH-PASMCs, whereas that of ROCK2 was markedly higher in IPAH-PASMCs than in normal-PASMCs. KD025 inhibited the accelerated proliferation of IPAH-PASMCs in a concentration-dependent manner (IC50 = 289 nM). Accelerated proliferation was also reduced by the siRNA knockdown of ROCK2. In MCT-PH rats, the expression of ROCK2 was up-regulated in PASMCs. Elevated right ventricular systolic pressure in MCT-PH rats was attenuated by KD025 (1 mg/kg/day). These results strongly suggest that enhanced ROCK2 signaling is involved in the pathogenic mechanism underlying the development of PAH, including accelerated PASMC proliferation and vascular remodeling in patients with PAH. Therefore, ROCK2 may be a novel therapeutic target for the treatment of PAH.

Background/Aim. Energy drinks (EDs) are widely used by athletes as ergogenic agents and Red Bull? is one of the most consumed EDs among them. The aim of this study was to determine the acute and chronic effects of Red Bull? on cardiodynamics and parameters of oxidative stress in physically trained rats. Methods. Rats were subjected to a swimming practice (1h a day, 5 days a week, for 4 weeks). They were divided into 4 groups: rats that did not consume ED either before swimming or prior to sacrificing; rats that did not consume ED before swimming but did consume ED 30 min prior to sacrificing; rats that consumed ED 30 min before every swimming training but did not consume ED prior to sacrificing; rats that consumed ED 30 min before every swimming training and 30 min before sacrificing. After sacrificing, the hearts of the rats were isolated and perfused according to the Langendorff technique. The parameters of cardiac function were recorded, and also the levels of prooxidants were measured in the coronary effluent during coronary autoregulation. Results. Acute administration of the ED had a positive inotropic effect (manifested as a significantly higher level of the maximum and minimum rate of pressure development in the left ventricle), while chronic administration affected the isolated increase in systolic left ventricular pressure. The prooxidative effect of the ED was observed, which was more pronounced in chronic consumption. Conclusion. The main conclusion of our study is that chronic consumption of ED changes the cardiovascular response and redox status in acute consumption ED.

Background/Aim. Dysfunctions at the cellular, tissue, and organ level, which can result in death, are caused by metabolic changes and affection on the regulation of gene transcription and micro- and macrocirculation. The aim of the present study was to assess the impact of hyperbaric oxygenation (HBO) on isolated heart as well as on the oxidative status of rats with sepsis. Methods. The investigation included male Wistar albino rats classified into three groups: the first group was a control group (CTRL); the second group included animals exposed only to the induction of sepsis without HBO treatment (the Sepsis group), while the third group included animals treated with HBO after the induction of sepsis (the Sepsis + HBO group). For the induction of sepsis, fecal peritonitis model was used (3 mL/kg of fecal suspension administered intraperitoneally). After the induction of sepsis, the rats were exposed twice a day (on 12 hours) to HBO treatment at 2.8 atmospheres absolute (ATA) for 90 minutes over a period of 3 days. 72 h after the confirmation of sepsis, the animals were sacrificed and the hearts were retrogradely perfused on the Langendorff apparatus at a gradually increased coronary perfusion pressure (CPP = 40?120 cm H2O). The following parameters of heart function were continuously recorded: maximum and minimum rate of left ventricular pressure development (dp/dt max, dp/dt min); systolic and diastolic left ventricular pressure (SLVP and DLVP); heart rate (HR). Coronary flow (CF) was measured flowmetrically. Following oxidative stress markers were measured: nitrites (NO2?), superoxide anion radical (O2?), hydrogen peroxide (H2O2), index of lipid peroxidation (TBARS), activity of superoxide dismutase (SOD) and catalase (CAT) and the level of reduced glutathione (GSH). Results. There were no significant differences in dp/dt max, dp/dt min, SLVP and HR between the groups. CF was statistically significantly higher (p < 0.01) in the sepsis group. The values of all cardiac oxidative markers were lower in the sepsis + HBO group (p < 0.05), while systemic pro-oxidative and antioxidative parameters were unchanged. Conclusion. Our results showed that HBO treatment was not associated with improved cardiac function and coronary perfusion, while expressed promising beneficial effects on cardiac oxidative stress.

Ivabradine (Iva), a heart rate reducing agent that specifically inhibits the pacemaker I(f) ionic current, has been demonstrated to be cardioprotective in many cardiovascular diseases. Autophagy is an evolutionarily conserved metabolic process that regulates cardiac homeostasis. This study is aimed to explore whether autophagy is functionally involved in the cardioprotective effect of Iva in a rat model of myocardial infarction (MI). We observed that Iva treatment (po, 10 mg/kg/day) showed significant recovery on the hemodynamics parameters in MI rats, including left ventricular systolic pressure, left ventricular end diastolic pressure, and maximal ascending/descending rate of left ventricular pressure. Also, Iva treatment dramatically decreased infarct size, inhibited myocardial apoptosis, and reduced the levels of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in MI rats. Moreover, Iva treatment enhanced autophagy and inhibited PI3K/AKT/mTOR/p70S6K pathway in MI rats. Simultaneously, we observed that autophagy enhancer rapamycin (ip, 10 mg/kg/day) showed similar cardioprotective effects with Iva. Furthermore, we observed that addition of autophagy inhibitor 3-methyladenine (ip, 10 mg/kg/day) counteracted the therapeutic effect of Iva, addressing that Iva attenuated post-MI cardiac injury by enhancing autophagy. In summary, these findings demonstrated that Iva attenuated MI in rats by enhancing autophagy, and PI3K/AKT/mTOR/p70S6K pathway might be involved in the process. Autophagy activation by Iva may be a potential therapeutic strategy for the treatment of MI., Graphical Abstract

Our aim was to assess the regional right ventricular (RV) shape changes in pressure and volume overload conditions and their relations with RV function and mechanics. The end-diastolic and end-systolic RV endocardial surfaces were analyzed with three-dimensional echocardiography (3DE) in 33 patients with RV volume overload (rToF), 31 patients with RV pressure overload (PH), and 60 controls. The mean curvature of the RV inflow (RVIT) and outflow (RVOT) tracts, RV apex and body (both divided into free wall (FW) and septum) were measured. Zero curvature defined a flat surface, whereas positive or negative curvature indicated convexity or concavity, respectively. The longitudinal and radial RV wall motions were also obtained. rToF and PH patients had flatter FW (body and apex) and RVIT, more convex interventricular septum (body and apex) and RVOT than controls. rToF demonstrated a less bulging interventricular septum at end-systole than PH patients, resulting in a more convex shape of the RVFW (r = − 0.701, p

Background: Instantaneous wave-free ratio (iFR)-guided physiological assessment has been shown to be non-inferior to fractional flow reserve (FFR)-guided assessment for deciding best treatment strategy for angiographically intermediate stenosis. The diagnostic accuracy of iFR compared to FFR reported in various studies is around 80%. Many factors can lead to iFR/FFR discordance, though underlying physiological mechanism of discordance and its associated factors have not been fully evaluated. The effect of left ventricle end diastolic pressure (LVEDP) on iFR/FFR discordance is unknown and needs further evaluation. Methods: We performed a single center, non-randomized, both retrospective and prospective study. A total of 65 patients with intermediate coronary stenosis undergoing physiological assessment were included in the study. Patients were assigned to two groups (normal LVEDP and high LVEDP group) based on LVEDP cutoff of 15 mm Hg. iFR and FFR were measured for each patient and iFR/FFR results were compared between the two groups. Results: A significantly large number of patients in elevated LVEDP group had iFR/FFR discordance compared to normal LVEDP group (42.8% vs. 6.7%, P = 0.001). More patients with acute coronary syndrome (ACS) had discordance compared to stale coronary artery disease (CAD) patients (53% vs. 15%, P = 0.003). Conclusions: Elevated LVEDP can affect iFR and FFR measurements and can lead to discordance. Further studies are required to determine effect of elevated LVEDP on iFR/FFR discordance and whether such discordance is clinically relevant. “Normal range” iFR results should be cautiously interpreted in patients with elevated LVEDP, especially those with ACS. Cardiol Res. 2021;12(2):117-125 doi: https://doi.org/10.14740/cr1230

Context Xinmai 'an tablet has been used to improve myocardial blood supply. Recently, some compounds from its formula have shown that they can treat pulmonary arterial hypertension (PAH). Objective This study investigates the effects of Xinmai 'an extract (XMA) on PAH and further tests the co-therapeutic enhancement with sildenafil (SIL). Materials and methods Pulmonary artery smooth muscle cells were subjected to stimulation with SIL (12.5 μM) and XMA (250 μg/mL) for 48 h. Sprague–Dawley rats were randomly grouped into eight groups (n = 8 per group): (I) control group received saline; (II) MCT group received MCT (60 mg/kg); (III) SIL-Low group received MCT + SIL at 10 mg/kg/day; (IV) SIL-high group received MCT + SIL at 30 mg/kg/day; (V) XMA-High group received MCT + XMA at 251.6 mg/kg/day; (VI) SIL (Low)+XMA (Low) group received SIL (10 mg/kg) + XMA at 62.9 mg/kg/day; (VII) SIL (Low)+XMA (Medium) group received SIL (10 mg/kg) + XMA at 125.8 mg/kg/day; (VIII) SIL (Low)+XMA (High) group received SIL (10 mg/kg) + XMA at 251.6 mg/kg/day. Both XMA and SIL were given by gavage and were maintained daily for 2 weeks. Results XMA could improve SIL’s efficacy in the treatment of PAH by decreasing cell viability more effectively at non-cytotoxic concentrations (250 μg/mL) and reducing Right Ventricular Systolic Pressure (RVSP) in PAH rat. Potential mechanisms might at least in part be through activating the MAPK signalling pathway. Discussion and conclusions The combination of XMA and SIL can improve the efficacy of pulmonary hypertension and reduce the dosage of SIL.

Heart diseases are one of the leading causes of death worldwide, and a dysfunction of the cardiac electrical mechanisms is responsible for a significant portion of these deaths. One of these mechanisms, the mechano-electric feedback (MEF), is the electrical response of the heart to local mechanical changes in the environment. This electrical response, in turn, leads to macroscopic changes in heart function. In this paper, we demonstrate that the MEF plays a crucial role in mechanical generation and recovery from arrhythmia which has been observed in experimental studies. To this end, we investigate the cardiac response to a mechanical stimulation using a minimal, multiscale model of the heart which couples the organ level dynamics (left ventricular pressure and volume) and contractile dynamics. By including a mechanical stimulation into the model as a (short, sudden) impulse in the muscle microscale stress, we investigate how the timing, amplitude and duration of the impulse affect the cardiac cycle. In particular, when introduced in the diastolic period of the cardiac cycle, the pulse rate can be stabilised, and ectopic beats and bifurcation can be eliminated, either temporarily or permanently. The stimulation amplitude is a key indicator to this response. We find an optimal value of the impulse amplitude above or below which the impulse maximises the stabilisation. As a result a dysfunction of the MEF can be helped using a mechanical stimulation, by allowing the heart to recover its pumping power. On the other hand, when the mechanical stimulation is introduced towards the end of systole, arrhythmia can be generated.

A 63-year-old man presented with hemoptysis and progressive dyspnea. His echocardiogram was concerning for pulmonary hypertension (PH) and CT chest showed fibrosing mediastinitis with possible cardiac involvement. Right heart catheterization revealed PH at rest and worsened with exercise. CT findings and simultaneous measurement of pulmonary capillary wedge pressure (PCWP), left atrial pressure, and left ventricular pressure helped diagnose pulmonary vein (PV) stenosis as the etiology of his PH. Both upper pulmonary veins were stented, and repeat exercise hemodynamic study revealed a substantial reduction in pulmonary arterial pressure with improvement in subjective dyspnea, cardiac output reserve, mechanical efficiency, and ventilatory efficiency. Repeat right upper PCWP normalized, consistent with resolution of the PV stenosis.

Background The receptor for advanced glycation end products (RAGE), a transmembrane receptor belonging to the immunoglobulin superfamily, is overexpressed in pulmonary artery smooth muscle cells (PASMCs) in patients with pulmonary arterial hypertension (PAH) and is implicated in the etiology of PAH. Recently, we reported that RAGE-aptamer, a short and single-stranded DNA directed against RAGE, inhibited an inappropriate increase in cultured PASMCs in PAH. The aim of this study was to determine the efficacy of RAGE-aptamer in monocrotaline-induced PAH in rats. Methods and Results Rats were assigned to either an untreated control group, a group that received continuous subcutaneous administration of RAGE-aptamer immediately after monocrotaline injection, or a group that received control-aptamer immediately after monocrotaline injection. All rats survived 21 days after injection of monocrotaline and control-aptamer or RAGE-aptamer. Injection of monocrotaline with continuous subcutaneous delivery of control-aptamer resulted in higher right ventricular systolic pressure compared with controls. This increase was attenuated by continuous subcutaneous delivery of RAGE-aptamer. The proportion of small pulmonary arteries with full muscularization was greater in the monocrotaline and control-aptamer group than in the control group. Continuous subcutaneous delivery of RAGE-aptamer significantly reduced the percentage of small pulmonary arteries with full muscularization. Conclusions Continuous subcutaneous delivery of RAGE-aptamer suppresses development of monocrotaline-induced PAH in rats. Inhibition of RAGE ameliorates muscularization of small pulmonary arteries. Treatment with RAGE-aptamer might be a new therapeutic option for PAH.

Purpose: Increasing worldwide demand for cardiac transplantation has spurred new developments to increase the donor pool. Normothermic preservation of heart grafts for transplantation is an emerging strategy to improve the utilization of marginal grafts. Hyperpolarized MR using metabolic tracers such as [1-13C]pyruvate, provide a novel means of investigating metabolic status without the use of ionizing radiation. We demonstrate the use of this methodology to examine ex vivo perfused porcine heart grafts. Methods: Hearts from three 40-kg Danish domestic pigs were harvested and subsequently perfused in Langendorff mode under normothermic conditions, using an MR-compatible perfusion system adapted to the heart. Proton MRI and hyperpolarized [1-13C]pyruvate were used to investigate and quantify the functional and metabolic status of the grafts. Results: Hearts were perfused with whole blood for 120 min, using a dynamic contrast-enhanced perfusion experiment to verify successful myocardial perfusion. Hyperpolarized [1-13C]pyruvate MRI was used to assess the metabolic state of the myocardium. Functional assessment was performed using CINE imaging and ventricular pressure data. High lactate and modest alanine levels were observed in the hyperpolarized experiment. The functional assessment produced reduced functional parameters. This suggests an altered functional and metabolic profile compared with corresponding in vivo values. Conclusion: We investigated the metabolic and functional status of machine-perfused porcine hearts. Utilizing hyperpolarized methodology to acquire detailed myocardial metabolic information—in combination with already established MR methods for cardiac investigation—provides a powerful tool to aid the progress of donor heart preservation.

BACKGROUND In 2016, the American Society of Echocardiography (ASE) released guidelines for identifying left ventricular (LV) diastolic dysfunction (DD), but its ability to detect early hemodynamic abnormalities is not well established, especially in the setting of subclinical coronary artery disease (CAD). We hypothesize that the accuracy of ASE categorization of early LVDD is affected by knowledge of whether CAD history is present. METHODS We studied 34 patients (age 62 ± 7 years) with NYHA class I to II symptoms and with transthoracic echocardiography without findings suggesting myocardial disease (all with preserved LV ejection fraction), who underwent cardiac catheterization with high-fidelity LV pressure measurement. Echocardiographic images were evaluated for LVDD using ASE algorithm without and with knowledge of CAD history and angiography findings. CAD was considered as having DD for the algorithm. RESULTS CAD was identified in 22 patients at catheterization (65%). Using ASE guidelines without including history of CAD or angiographic results, 29 patients were DD-, 3 were DD+ (all grade II), and 2 were indeterminate. Inclusion of CAD history recategorized 59% (n = 20) patients to DD+ (all grade I) from DD- (P

Aims We sought to investigate the time course of cardiac disorders after catheter ablation for atrial fibrillation (AF) in patients with coexisting heart failure (HF) during long‐term follow‐up. Methods and results We analysed consecutive 280 patients undergoing first‐time catheter ablation for AF who had coexisting HF, which was defined as prior HF hospitalization, estimated right ventricular systolic pressure ≥45 mmHg, or B‐type natriuretic peptide (BNP) ≥200 pg/dL before the procedure. The primary endpoints were improvements in left ventricular ejection fraction (LVEF), E/e′, BNP, left atrial dimension (LAD), and mitral regurgitation (MR) at 1 year. The secondary endpoints were serial changes of LVEF, E/e′, BNP, LAD, and MR at 6 months, 1 year, and 5 years and cumulative incidence of HF hospitalization. During the mean follow‐up of 5.1 ± 3.0 years, 70.7% of patients were free from recurrent AF. Among patients with LVEF

Left ventricular (LV) global longitudinal strain (GLS) has emerged as a significant prognostic marker in patients after myocardial infarction (MI). Although elevated LV filling pressure after MI might alter GLS, direct evidence for this is lacking. This study aimed to clarify the association between GLS and LV filling pressure in a large animal MI model. A total of 104 Yorkshire pigs underwent both echocardiographic and hemodynamic assessments 1–4 wk after induction of large anterior MI. GLS was measured in the apical four-chamber view using a semiautomated speckle-tracking software. LV pressure-volume relationship was invasively measured using a high-fidelity pressure-volume catheter. GLS >−14% was considered impaired. Compared with pigs with LV ejection fraction (LVEF) >40% and preserved GLS (n = 29), those with LVEF >40% and impaired GLS (n = 37) and those with LVEF ≤40% (n = 38) had significantly higher LV end-diastolic pressure (15.5 ± 5.5 vs. 19.7 ± 5.8 and 19.6 ± 6.6 mmHg; P = 0.008 and P = 0.026, respectively) and higher LV mean diastolic pressure (7.1 ± 2.9 vs. 10.4 ± 4.5 and 11.1 ± 5.4 mmHg; P = 0.013 and P = 0.002, respectively). GLS was modestly correlated with τ (r = 0.21, P = 0.039) and slope of LV end-diastolic pressure–volume relationship (r = 0.43, P < 0.001). Impaired GLS was associated with higher LV end-diastolic and mean-diastolic pressures after adjusting for LVEF and baseline characteristics (P = 0.026 and P = 0.001, respectively). Impaired GLS assessed by speckle-tracking echocardiography was associated with elevated LV filling pressure after MI. GLS has an incremental diagnostic value for detecting elevated LV filling pressure and may be particularly useful for evaluating post-MI patients with preserved LVEF. NEW & NOTEWORTHY Strain analysis was performed in 104 pigs after MI, and its relationship to invasive hemodynamic measurements was studied. Impaired longitudinal strain was associated with high ventricular filling pressure independent of LVEF in post-MI setting. Global longitudinal strain is a potential prognostic marker after MI.

To assess pulmonary artery pressure and cardiac remodeling in pregnancy in women with pulmonary hypertension and compare these findings with studies done beyond three months postpartum.Pregnant women with pulmonary hypertension from 2006 to 2017 were studied. Pulmonary hypertension was diagnosed when the pulmonary artery pressure exceeded 30 mmHg as estimated by right ventricular systolic pressure (RVSP) on echocardiography or 20 mmHg measured directly by mean pulmonary artery pressure (PAPm) with right-heart catheterization (RHC). Disease severity was assigned using threshold cutoffs. Indices of cardiac remodeling were compared during pregnancy after 20 weeks' gestation and again beyond three months postpartum when available. Pulmonary artery pressures obtained by echocardiography versus right-heart catheterization were also compared.Forty-six pregnancies complicated by pulmonary hypertension in 41 women were identified. The study included 43 pregnancies that resulted in a livebirth. There were 20 women in whom studies were performed after 20 weeks' gestation and again at least 3 months postpartum or later. Pulmonary artery pressures determined during pregnancy versus beyond three months postpartum were not significantly different when measured by echocardiography (RVSP 53.5 ± 20.5 mmHg and 46.7 ± 20.4 mmHg,Pulmonary artery pressures did not appreciably change during pregnancy after 20 weeks' gestation compared with pressures measured again beyond three months postpartum. Women with pulmonary hypertension did not show evidence of remodeling of left ventricular mass or relative wall thickness when measured in pregnancy after 20 weeks' gestation compared with beyond three months postpartum in this limited cohort. These findings suggest that cardiac remodeling in women with pulmonary hypertension is different from that of normally pregnant women and confirms the need for careful long-term follow-up.

Non-ST-segment-elevation acute coronary syndrome (NSTE-ACS) patients with normal left ventricular (LV) ejection fraction (LVEF) and wall motion require a non-invasive tool to detect LV risk areas. This study utilized non-invasive LV pressure–strain loops to evaluate territorial myocardial work efficiency (WE) for identifying obstructive coronary artery stenosis, in patients with non-obstructive or obstructive coronary artery stenosis NSTE-ACS, the latter with or without occlusion. Global and territorial longitudinal strain (LS) analyses were performed via speckle-tracking imaging before coronary angiography. LV pressure–strain loops estimated global and territorial myocardial work index (MWI), constructive work (CW), wasted work (WW), and WE. Receiver operating characteristic curve analysis was used to determine the optimal cutoff value of independent parameters to detect obstructive coronary artery stenosis. Compared with non-obstructive, obstructive coronary artery stenosis showed significantly lower global and territorial LS, MWI, CW, and WE, and higher WW. Territorial LS, MWI, CW, and WE were significantly worse in territories of coronary occlusion. Territorial WE was the best parameter for predicting obstructive coronary artery stenosis (AUC 0.80, cutoff

In Anderson–Fabry disease (AFD) the impact of left ventricular (LV) function on cardiac outcome is unknown. Noninvasive LV pressure–strain loop analysis is a new echocardiographic method to estimate myocardial work (MW). We aimed to evaluate whether LV function was associated with outcome and whether MW had a prognostic value in AFD. Ninety-six AFD patients (41.8 ± 14.7 years, 43.7% males) with normal LV ejection fraction were retrospectively evaluated. Inclusion criteria were sinus rhythm and ≥ 2-year follow-up. Standard echocardiography measurements, myocardial mechano-energetic efficiency (MEE) index, global longitudinal strain (GLS) and MW were evaluated. Adverse cardiac events were defined as composite of cardiac death, malignant ventricular tachycardia, atrial fibrillation and severe heart failure development. During a median follow-up of 63 months (interquartile range 37–85), 14 events occurred. Patient age, cardiac biomarkers, LV mass index, left atrium volume, E/Ea ratio, LV ejection fraction, MEE index, GLS and all MW indices were significantly related to adverse outcome at univariate analysis. After adjustment for clinical and echocardiographic parameters, which were significant at univariate analysis, GLS and MW resulted independent predictors of adverse events (p

BACKGROUND Donation after circulatory death (DCD) represents an increasing source of organs. However, evaluating the suitability of DCD hearts for transplantation represents a challenge. Contractile function is the ultimate determinant of recovery. We developed a novel technique in an ex vivo rig for the measurement of contractility using intraventricular balloons. We compared this technique with the measurement of lactate metabolism, the current gold standard. METHODS Human DCD (n = 6) and donation after brain death (n = 6) hearts were preserved by perfusion with a cold oxygenated crystalloid solution for 4 h, transferred to a blood perfusion rig at 37 °C where balloons were inserted into the left (LV) and right (RV) ventricles to measure developed pressure (DP = systolic minus diastolic). Perfusate lactate levels were measured for metabolic assessment. Concordance between LVDP and lactate was assessed during 4 h using cutoffs for LVDP of 70 mm Hg and for lactate of 10 mmol/L. RESULTS Measurements of contractile function (LVDP) and metabolism (lactate levels) were deemed concordant in 7 hearts with either a high LVDP (mean 100 mm Hg) with low lactate (mean 6.7 mmol/L)) or a low LVDP (15 mm Hg) with high lactate (mean 17.3 mmol/). In the remaining 5 hearts, measurements were deemed discordant: 4 hearts had high LVDP (mean 124 mm Hg), despite high lactate levels 17.3 mmol/L) and 1 had low LVDP (54 mm Hg) but low lactate (6.9 mmol/L). CONCLUSIONS The intraventricular balloon technique provides useful information regarding contractile recovery of donor hearts that if combined with lactate metabolism has potential application for the evaluation of DCD and marginal donation after brain death hearts before transplant.

Cardiac inflammation and fibrosis triggered by left ventricular pressure overload are the major causes of heart dysfunction. Differentiated embryonic chondrocyte gene 1 (Dec1) is a basic helix-loop-helix transcription factor that is comprehensively involved in inflammation and tissue fibrosis, but its role in cardiac hypertrophy remains unclear. This study explored the effects of Dec1 on cardiac fibrosis, inflammation, and apoptosis in hypertrophic conditions. Transverse aortic constriction (TAC) was performed to induce cardiac hypertrophy in wild-type (WT) mice and in Dec1 knock out (KO) mice for 4 weeks. Using the TAC mouse model, prominent differences in cardiac hypertrophy at the morphological, functional, and molecular levels were delineated by Masson’s Trichrome and TUNEL staining, immunohistochemistry, RT-PCR and Western Blot. DNA microarray and microRNA (miRNA) array analyses were carried out to identify gene and miRNA expression patterns. Dec1KO mice exhibited a more severe hypertrophic heart, whereas WT mice showed a more pronounced perivascular fibrosis after TAC at 4 weeks. The Dec1 deficiency promoted M2 phenotype macrophages. Dec1KO TAC mice showed fewer apoptotic cells than WT TAC mice. APEX1, WNT16, FGF10 and MMP-10 were differentially expressed according to DNA microarray analysis and expression levels of those genes and the corresponding miRNAs (miR-295, miR-200 b, miR-130a, miR-92a) showed the same trends. Furthermore, luciferase reporter assay confirmed that FGF10 is the direct target gene of miR-130. In conclusion, a Dec1 deficiency protects the heart from perivascular fibrosis, regulates M1/M2 macrophage polarization and reduces cell apoptosis, which may provide a novel insight for the treatment of cardiac hypertrophy.

Supplemental Digital Content is Available in the Text., Heart failure (HF) affects around 100 million people and is a staggering burden for health care system worldwide. Rapid and sustained activation of inflammatory response is an important feature of HF after myocardial infarction. Sympathetic overactivation is also an important factor in the occurrence and progression of HF. The beneficial effect of renal denervation (RDN) has been demonstrated in HF. In the current study, we hypothesized that RDN improves cardiac function in HF canine models due to acute myocardial infarction (AMI) and reduced inflammation might be involved. Twenty-four beagles were randomized into the control (n = 8), HF (n = 8), and HF + RDN group (n = 8). The HF model after AMI was established by embolization the anterior descending distal artery with anhydrous ethanol in the HF and HF + RDN group. Bilateral renal artery ablation was performed in the HF + RDN group. Cardiac function, serum creatine kinase, creatine kinase-MB and NT-Pro BNP level, and expression of inflammation-related proteins in myocardial were examined. Because the paraventricular nucleus of the hypothalamus might be involved in inflammation-induced central neural excitation in HF and plays an important role in regulating extracellular fluid volume and sympathetic activity, expression of inflammation-related proteins in hypothalamus was also examined. AMI and post-AMI HF model was created successfully. Compared with the HF group, dogs in the HF + RDN group showed better cardiac function 4 weeks after AMI: lower left ventricular end-diastolic pressure, left ventricular end-diastolic dimension, and left ventricular end-systolic dimension and higher LEVF and left ventricular systolic pressure (P < 0.05 for all) were observed in the HF + RDN group. In addition, dogs in the HF + RDN group had slightly less ventricular fibrosis. Interestingly, RDN had lower expression of inflammation-related proteins including interleukin-6, tumor necrosis factors-α, nuclear factor κB, and monocyte chemotactic protein 1 (P < 0.05 for all) in both myocardial tissue and hypothalamus. RDN can improve cardiac function in dogs with HF after myocardial infarction. Our results suggested that RDN might affect cytokine-induced central neural excitation in HF and later affect sympathetic activity. Our results suggested a potential beneficial mechanism of RDN independent of mechanism involving renal afferent and efferent sympathetic nerves.

Aims Emipagliflozin (EMPA) is a potent inhibitor of the renal sodium-glucose co-transporter 2 (SGLT2) and an effective treatment for type-2 diabetes. In patients with diabetes and heart failure, EMPA has cardioprotective effects independent of improved glycaemic control, despite SGLT2 not being expressed in the heart. A number of non-canonical mechanisms have been proposed to explain these cardiac effects, most notably an inhibitory action on cardiac Na+/H+ exchanger 1 (NHE1), causing a reduction in intracellular [Na+] ([Na+]i). However, at resting intracellular pH (pHi), NHE1 activity is very low and its pharmacological inhibition is not expected to meaningfully alter steady-state [Na+]i. We re-evaluate this putative EMPA target by measuring cardiac NHE1 activity. Methods and results The effect of EMPA on NHE1 activity was tested in isolated rat ventricular cardiomyocytes from measurements of pHi recovery following an ammonium pre-pulse manoeuvre, using cSNARF1 fluorescence imaging. Whereas 10 µM cariporide produced near-complete inhibition, there was no evidence for NHE1 inhibition with EMPA treatment (1, 3, 10, or 30 µM). Intracellular acidification by acetate-superfusion evoked NHE1 activity and raised [Na+]i, reported by sodium binding benzofuran isophthalate (SBFI) fluorescence, but EMPA did not ablate this rise. EMPA (10 µM) also had no significant effect on the rate of cytoplasmic [Na+]i rise upon superfusion of Na+-depleted cells with Na+-containing buffers. In Langendorff-perfused mouse, rat and guinea pig hearts, EMPA did not affect [Na+]i at baseline nor pHi recovery following acute acidosis, as measured by 23Na triple quantum filtered NMR and 31P NMR, respectively. Conclusions Our findings indicate that cardiac NHE1 activity is not inhibited by EMPA (or other SGLT2i’s) and EMPA has no effect on [Na+]i over a wide range of concentrations, including the therapeutic dose. Thus, the beneficial effects of SGLT2i’s in failing hearts should not be interpreted in terms of actions on myocardial NHE1 or intracellular [Na+]., Graphical Abstract

Aims\ud \ud The clinical reliability of echocardiographic surrogate markers of left ventricular filling pressures (LVFPs) across different cardiovascular pathologies remains unanswered. The main objective was to evaluate the evidence of how effectively different echocardiographic indices estimate true LVFP.\ud \ud \ud Methods and results\ud \ud Design: this is a systematic review and meta‐analysis. Data source: Scopus, PubMed and Embase. Eligibility criteria for selecting studies were those that used echocardiography to predict or estimate pulmonary capillary wedge pressure or left ventricular end‐diastolic pressures. Twenty‐seven studies met criteria. Only eight studies (30%) reported both correlation coefficient and bias between non‐invasive and invasively measured LVFPs. The majority of studies (74%) recorded invasive pulmonary capillary wedge pressure as a surrogate for left ventricular end‐diastolic pressures. The pooled correlation coefficient overall was r = 0.69 [95% confidence interval (CI) 0.63–0.75, P < 0.01]. Evaluation by cohort demonstrated varying association: heart failure with preserved ejection fraction (11 studies, n = 575, r = 0.59, 95% CI 0.53–0.64) and heart failure with reduced ejection fraction (8 studies, n = 381, r = 0.67, 95% CI 0.61–0.72).\ud \ud \ud Conclusions\ud \ud Echocardiographic indices show moderate pooled association to invasively measured LVFP; however, this varies widely with disease state. In heart failure with preserved ejection fraction, no single echocardiography‐based metric offers a reliable estimate. In heart failure with reduced ejection fraction, mitral inflow‐derived indices (E/e′, E/A, E/Vp, and EDcT) have reasonable clinical applicability. While an integrated approach of several echocardiographic metrics provides the most promise for estimating LVFP reliably, such strategies need further validation in larger, patient‐specific studies.

Several interleukins (ILs) have been shown to be involved in aging, but the effects of IL-6 on aging-related cardiac dysfunction remain unknown. In this study, the expression and sources of cardiac IL-6 in aging hearts were investigated for the first time. The results showed that cardiac IL-6 expression in mice gradually increased with age, and the expression at 16 months, 20 months and 25 months was higher than that at 3 months. In addition, cardiac macrophages (Møs) were shown to be the main sources of IL-6 in aging mice. IL-6 knockout (KO) significantly alleviated cardiac dysfunction, increased M2 macrophage (Mø2) differentiation, reduced M1 macrophage (Mø1) differentiation and protected against cardiomyocyte apoptosis in aging mice. IL-6 KO also reversed the stimulatory effect of doxorubicin (DOX) treatment on Mø1s and the inhibitory effect of DOX treatment on Mø2s in vitro. Furthermore, the mRNA expression of both aging markers and apoptosis-related markers was markedly inhibited by IL-6 KO. Our results suggest that aging can be significantly reversed by IL-6 KO and that the mechanisms of this effect are related to alleviation of Mø1/Mø2 imbalance and protection against apoptosis in cardiomyocytes.

Radix Aconiti Lateralis Preparata (Fuzi) is a traditional Chinese medicine. Its alkaloids are both cardiotonic and cardiotoxic; however, the underlying mechanisms are unclear. Compatibility testing and processing are the primary approaches used to reduce the toxicity of aconite preparations. The purpose of this study was to compare the effects of crude Fuzi (CFZ), CFZ combined with Glycyrrhiza (Gancao) (CFZ+GC), and prepared materials of CFZ (PFZ) on heart failure (HF) in C57BL/6J mice and explore the potential mechanisms of action of CFZ. Transverse aortic constriction (TAC) was used to generate the HF state, and CFZ (1.5 g·mL−1), PFZ (1.5 g·mL−1), or CFZ+GC (1.8 g·mL−1) was orally administered to the HF-induced mice daily. For the subsequent 8 weeks, hemodynamic indicators, ventricular pressure indices, and mass indices were evaluated, and histopathological imaging was performed. CFZ, CFZ+GC, and PFZ significantly improved left ventricular function and structure and reduced myocardial damage. CFZ+GC was more effective than CFZ and PFZ, whereas CFZ had higher toxicity than CFZ+GC and PFZ. CFZ and CFZ+GC attenuated ischemia-induced inflammatory responses and also inhibited Toll-like receptor-4 (TLR4) and nuclear factor kappa beta (NF-κB) action in the heart. Moreover, mass spectrometry analysis revealed a decrease in the levels of toxic components of CFZ+GC, whereas those of the protective components were increased. This study suggested that GC reduces the toxicity and increases the efficacy of CFZ on HF induced by TAC. Furthermore, GC+CFZ reduces the risk of HF by ameliorating the inflammation response, which might be partially related to the inhibition of the TLR4/NF-κB pathway.

Background: There is some experimental data on the effect exerted by some steroid derivatives against ischemia/reperfusion injury; however, the molecular mechanism is very confusing, perhaps this phenomenon could be due to the protocols used and/or differences in the chemical structure of each one of the steroid derivatives. Objective: The aim of this study was to synthesize a new bis-steroid-methanocyclobutanaphthalene- dione derivative using some tools chemical. Methodology: The biological activity exerted by the bis-steroid-methanocyclobutanaphthalene- dione derivative against ischemia/reperfusion injury was evaluated in an isolated heart model using noradrenaline, milrinone, dobutamine, levosimendan, and Bay-K- 8644 as controls. In addition, other alternative experiments were carried out to evaluate the biological activity induced by the bis-steroid-methanocyclobuta-naphthalene-dione derivative against left ventricular pressure in the absence or presence of nifedipine. Results: The results showed that 1) the bis-steroid-methanocyclobuta-naphthalene-dione derivative significantly decreases the ischemia-reperfusion injury translated as a decrease in the the infarct area in a similar manner to levosimendan drug; 2) both bis-steroidmethanocyclobuta- naphthalene-dione and Bay-K-8644 increase the left ventricular pressure and 3) the biological activity exerted by bis-steroid-methanocyclobuta-naphthalenedione derivative against left ventricular pressure is inhibited by nifedipine. Conclusion: In conclusion, the bis-steroid-methanocyclobuta-naphthalene-dione derivative decreases the area of infarction and increases left ventricle pressure via calcium channels activation; this phenomenon could constitute a new therapy for ischemia/reperfusion injury.

OBJECTIVES We aimed to describe the anatomic distribution of periarterial pulmonary sympathetic nerves and to observe the long-term morphometric and functional changes after pulmonary artery denervation (PADN), a novel therapy for pulmonary arterial hypertension (PAH). METHODS A total of 45 beagles were divided into a sympathetic innervation group (n = 3, 33.3% were females), a PAH group (n = 35, 34.3% were females) and a control group (n = 7, 28.5% were females). The PAH group was randomly divided into no-PADN (n = 7), instant-PADN (n = 7), 1M-PADN (n = 7), 2M-PADN (n = 7) and 3M-PADN (n = 7) subgroups. The sympathetic innervation group was sacrificed to reveal the sympathetic innervation of pulmonary arteries. PAH was induced by injecting dehydromonocrotaline (DHMCT) through the right atrium. The pulmonary capillary wedge pressure, right ventricular systolic pressure, right ventricular mean pressure, pulmonary artery systolic pressure and pulmonary artery mean pressure of each group were continuously measured. The cardiac output was detected to calculate the pulmonary vascular resistance. PAH and control groups were subjected to immunofluorescence assay, sympathetic nerve conduction velocity measurement and transmission electron microscopy. RESULTS The no-PADN group had significantly higher PVSP, PVMP, pulmonary artery systolic pressure, pulmonary artery mean pressure and pulmonary vascular resistance but lower cardiac output than those of the control group (P CONCLUSIONS PADN effectively relieved dehydromonocrotaline-induced canine PAH and decreased sympathetic nerve conduction velocity.

Protamine causes cardiac depression, which may be mediated by tumor necrosis factor alpha (TNF-α). Ulinastatin, a human urinary protease inhibitor, inhibits TNF-α. Here, we aimed to investigate whether ulinastatin prevented protamine-induced myocardial depression by inhibiting TNF-α. Rat hearts were perfused using a Langendorff system, and three protocols were followed. Protocol 1: The hearts were divided into saline, ulinastatin-low, and ulinastatin-high groups. Protamine was administered to each group, and myocardial contractility was the primary outcome. Protocol 2: The hearts were allotted to saline or ulinastatin group. Protamine was administered to each group. TNF-α expression in the coronary effluent and myocardial tissue was measured. Protocol 3: The hearts were allotted to saline and ulinastatin groups. Recombinant rat-TNF-α was administered to each group. Protamine alone reduced the maximum left ventricular pressure derivative (LV dP/dt max) by 45 ± 4%. In contrast, the reduction in LV dP/dt max was 4 ± 3% in the ulinastatin-high group. Compared with that in the saline group, the increase in TNF-α in the coronary effluent was attenuated in the ulinastatin group. Recombinant TNF-α alone reduced LV dP/dt max (- 21 ± 14%). In contrast, when TNF-α was added in the presence of ulinastatin, the decrease in LV dP/dt max was prevented significantly (- 3 ± 8%). We showed, for the first time, that ulinastatin protected against protamine-induced myocardial damage, both by inhibiting TNF-α synthesis and by directly preventing the cardiodepressant action of TNF-α.

Total and partial proximal catheter occlusions are well-known complications of ventriculoperitoneal shunts (VPS). When this occurs, surgeons often attempt to perform a shunt tap. However, the degree of obstruction in a proximal catheter that ultimately leads to shunt malfunction is unknown. We developed a benchtop model to simulate proximal catheter occlusion with two hydrostatic reservoirs connected by a VPS catheter system. The Centurion compass device was used to measure pressure across the valve digitally. Wires of varying diameters (equalling different occlusion percentages) were inserted into the catheter’s proximal end to stimulate obstruction. A mock shunt tap aspiration was then performed by incorporating a pressure transducer. As a general trend, pressure reading on the device decreases as occlusion increases. At higher levels of occlusion (> 45%), the blockage begins to significantly impede the flow through the catheter, and the pressure drops at a faster rate compared with lower occlusion percentages. The pressure reading converges quickly to 0 with increasing blockage after about 70%. The Centurion compass is able to detect large changes in pressure as evidenced by the major differences in pressure readings between no occlusion, 45%, and 84%. The shunt will not function at 84%. In order to determine the threshold for occlusion beyond which fluid cannot be withdrawn, we tested five levels of occlusion (0%, 33%, 63%, 84%, and 100%) at various aspiration pressures and determined that fluid can still be produced with 0–84% occlusion, but no fluid could be produced at 100% occlusion. We developed a model of proximal shunt obstruction and found that cerebrospinal fluid (CSF) flow through a VPS is unaffected up to 33% occlusion, begins to become impaired at 45% occlusion, and is miniscule at 84% occlusion. Shunt aspiration was not possible at 84% occlusion. Pressure measured at the reservoir is accurate and correlates with intracranial pressure (ICP) up to approximately 60% proximal occlusion. With partial occlusion up to 70%, ventricular pressure will dictate shunt function.

Objectives This study sought to evaluate a decision algorithm for the estimation of left ventricular filling pressure (LVFP) in patients with mitral annular calcification (MAC). Background In a single center study, Abudiab et al evaluated echocardiographic parameters to estimate LVFP in patients with MAC against invasive hemodynamic measurements and developed a decision algorithm which demonstrated high predictive accuracy. Methods Retrospectively, 55 patients (mean age 68.5 ± 11.5) with MAC and a left heart catheterization within 24 hours of an echocardiogram were identified. The decision algorithm was applied using echo data to classify patients as having normal or elevated LVFP which was then compared with the invasively obtained LVFP. Results The algorithm performed poorly at predicting pre-A LVFP as normal or high (P = .182). Accuracy for the algorithm was 0.59 [0.46, 0.72] (mean [95% CI]), sensitivity was 0.45 [0.28, 0.62], specificity was 0.73 [0.54, 0.86], false positive rate was 0.27 [0.14, 0.46], and false negative rate was 0.55 [0.38, 0.72]. E/A ratio, IVRT, and E/e'ratio showed no significant relationship to actual patient LVFP. Conclusions The Abudiab et al algorithm failed to demonstrate comparable sensitivity, specificity, and accuracy in our sample. Additional study is necessary to refine this tool prior to more widespread use in clinical practice.