Ventricular Pressure Research Articles

Abstract Tu094: p53 Regulates the Extent of Fibroblast Proliferation and Fibrosis in Left Ventricle Pressure Overload

Background: Cardiomyopathy is characterized by the pathological accumulation of resident cardiac fibroblasts that deposit ECM (extracellular matrix) and generate a fibrotic scar. However, the mechanisms that control the timing and extent of cardiac fibroblast proliferation and ECM production are not known, hampering the development of antifibrotic strategies to prevent heart failure. Methods: We used the Tcf21 (transcription factor 21) MerCreMer mouse line for fibroblast-specific lineage tracing and p53 (tumor protein p53) gene deletion. We characterized cardiac physiology and used single-cell RNA-sequencing and in vitro studies to investigate the p53-dependent mechanisms regulating cardiac fibroblast cell cycle and fibrosis in left ventricular pressure overload induced by transaortic constriction. Results: Cardiac fibroblast proliferation occurs primarily between days 7 and 14 following transaortic constriction in mice, correlating with alterations in p53-dependent gene expression. p53 deletion in fibroblasts led to a striking accumulation of Tcf21- lineage cardiac fibroblasts within the normal proliferative window and precipitated a robust fibrotic response to left ventricular pressure overload. However, excessive interstitial and perivascular fibrosis does not develop until after cardiac fibroblasts exit the cell cycle. Single-cell RNA sequencing revealed p53 null fibroblasts unexpectedly express lower levels of genes encoding important ECM proteins while they exhibit an inappropriately proliferative phenotype. in vitro studies establish a role for p53 in suppressing the proliferative fibroblast phenotype, which facilitates the expression and secretion of ECM proteins. Importantly, Cdkn2a (cyclin-dependent kinase inhibitor 2a) expression and the p16Ink4a-retinoblastoma cell cycle control pathway is induced in p53 null cardiac fibroblasts, which may eventually contribute to cell cycle exit and fulminant scar formation. Conclusions: This study reveals a mechanism regulating cardiac fibroblast accumulation and ECM secretion, orchestrated in part by p53-dependent cell cycle control that governs the timing and extent of fibrosis in left ventricular pressure overload.

Detecting elevated left ventricular end diastolic pressure from simultaneously measured femoral pressure waveform and electrocardiogram

Objective. Instantaneous, non-invasive evaluation of left ventricular end-diastolic pressure (LVEDP) would have significant value in the diagnosis and treatment of heart failure. A new approach called cardiac triangle mapping (CTM) has been recently proposed, which can provide a non-invasive estimate of LVEDP. We hypothesized that a hybrid machine-learning (ML) method based on CTM can instantaneously identify an elevated LVEDP using simultaneously measured femoral pressure waveform and electrocardiogram (ECG). Approach. We studied 46 patients (Age: 39–90 (66.4 ± 9.9), BMI: 20.2–36.8 (27.6 ± 4.1), 12 females) scheduled for clinical left heart catheterizations or coronary angiograms at University of Southern California Keck Medical Center. Exclusion criteria included severe mitral/aortic valve disease; severe carotid stenosis; aortic abnormalities; ventricular paced rhythm; left bundle branch and anterior fascicular blocks; interventricular conduction delay; and atrial fibrillation. Invasive LVEDP and pressure waveforms at the iliac bifurcation were measured using transducer-tipped Millar catheters with simultaneous ECG. LVEDP range was 9.3–40.5 mmHg. LVEDP = 18 mmHg was used as cutoff. Random forest (RF) classifiers were trained using data from 36 patients and blindly tested on 10 patients. Main results. Our proposed ML classifier models accurately predict true LVEDP classes using appropriate physics-based features, where the most accurate demonstrates 100.0% (elevated) and 80.0% (normal) success in predicting true LVEDP classes on blind data. Significance. We demonstrated that physics-based ML models can instantaneously classify LVEDP using information from femoral waveforms and ECGs. Although an invasive validation, the required ML inputs can be potentially obtained non-invasively.

Load Dependency of Ventricular Pump Function: Impact on the Non-Invasive Evaluation of the Severity and the Prognostic Relevance of Myocardial Dysfunction.

Ventricular pump function, which is determined by myocyte contractility, preload and afterload, and, additionally, also significantly influenced by heart rhythm, synchrony of intraventricular contraction and ventricular interdependence, explains the difficulties in establishing the contribution of myocardial contractile dysfunction to the development and progression of heart failure. Estimating myocardial contractility is one of the most difficult challenges because the most commonly used clinical measurements of cardiac performance cannot differentiate contractility changes from alterations in ventricular loading conditions. Under both physiological and pathological conditions, there is also a permanent complex interaction between myocardial contractility, ventricular anatomy and hemodynamic loading conditions. All this explains why no single parameter can alone reveal the real picture of ventricular dysfunction. Over time there has been increasing recognition that a load-independent contractility parameter cannot truly exist, because loading itself changes the myofilament force-generating capacity. Because the use of a single parameter is inadequate, it is necessary to perform multiparametric evaluations and also apply integrative approaches using parameter combinations which include details about ventricular loading conditions. This is particularly important for evaluating the highly afterload-sensitive right ventricular function. In this regard, the existence of certain reluctance particularly to the implementation of non-invasively obtainable parameter combinations in the routine clinical praxis should be reconsidered in the future. Among the non-invasive approaches used to evaluate ventricular function in connection with its current loading conditions, assessment of the relationship between ventricular contraction (e.g., myocardial displacement or deformation) and pressure overload, or the relationship between ejection volume (or ejection velocity) and pressure overload, as well as the relationship between ventricular dilation and pressure overload, were found useful for therapeutic decision-making. In the future, it will be unavoidable to take the load dependency of ventricular function much more into consideration. A solid basis for achieving this goal will be obtainable by intensifying the clinical research necessary to provide more evidence for the practical importance of this largely unsolved problem.

Echocardiographic Predictors of Readiness for Double Switch Operation and Postoperative Ejection Fraction in Patients With Congenitally Corrected Transposition of the Great Arteries Undergoing Left Ventricular Retraining

In patients with congenitally corrected transposition of the great arteries (ccTGA), assessment of readiness for the double switch operation (DSO) after pulmonary arterial band (PAB) placement involves cardiac magnetic resonance imaging (cMRI) to measure left ventricular ejection fraction (LVEF) and mass and cardiac catheterization (catheterization) to assess the ratio of left ventricular to right ventricular pressure (LV:RVp). The aims of this study were to describe the relationships between echocardiographic and catheterization and cMRI measures of readiness for DSO and to develop risk factors for left ventricular (LV) dysfunction after DSO on the basis of echocardiographic measures of ventricular-arterial coupling (VAC). Patients with ccTGA undergoing LV retraining at a DSO referral center were reviewed. LVEF measured by echocardiography was compared with that measured by cMRI, and LV:RVp measured by echocardiography was compared with that measured by catheterization using Bland-Altman analysis. The relationship between preoperative VAC markers and postoperative echocardiography was analyzed using ventricular end-systolic elastance (EES) and a novel marker consisting of the product of LVEF and LV:RVp (EFPR). Thirty-one patients with 56 evaluations for DSO were included, 24 of whom underwent DSO. Echocardiographic LVEF correlated well with cMRI LVEF (r=0.79), and Bland-Altman analysis slightly overestimated cMRI LVEF (mean difference,+3%). Echocardiographic LVEF had a moderate ability to identify normal cMRI LVEF (area under the curve, 0.80) and at an optimal cut point of echocardiographic LVEF threshold of 61%, there was 71% sensitivity and 76% specificity to detect cMRI LVEF≥55%. Echocardiographic LV:RVp correlated well with LV/RVp by catheterization (r=0.77) and slightly underestimated the catheterization value (mean difference, -0.11). Echocardiographic LV:RVp had a good ability to identify adequate LV:RVp by catheterization (area under the curve, 0.95) and at an optimal echocardiography cut point of 0.75 had 100% sensitivity and 85% specificity to detect a catheterization LV:RVp >0.9. Echocardiography-based criteria for DSO readiness (echocardiographic LVEF of 61% and LV:RVp of 0.75) demonstrated specificity of 97% and positive predictive value of 96% for published criteria of DSO readiness (cMRI LVEF of 55% and catheterization LV:RVp of 0.9). EES and EFPR correlated with post-DSO LVEF (ρ=0.72 and ρ=0.60, respectively). EFPR of 0.51 demonstrated 78% sensitivity and 100% specificity for post-DSO LV dysfunction (LVEF<55%). Age at first PAB also strongly correlated with post-DSO LVEF (ρ=0.75). No patient with first PAB at <1year of age exhibited post-DSO LV dysfunction. Echocardiographic measures of LVEF and LV:RVp are reliable indicators of reference standard modalities and can guide management during retraining. The preoperative VAC markers EES and EFPR may be useful markers of post-DSO LV dysfunction. Values of echocardiographic LV:RVp >0.75 are likely to meet pressure-generation criteria for DSO and should be considered for referral to catheterization and cMRI evaluation for DSO. PAB placement before 1year of life may optimize LV outcomes in patients considered for DSO.

Exercise Preconditioning Preserves Cardiac Function and Enhances Cardiac Recovery Following Dobutamine Stimulation in Doxorubicin-Treated Rat Hearts.

Exercise preconditioning has been shown to protect against doxorubicin (DOX)-induced cardiac dysfunction when hearts are maintained under resting conditions. However, it is unclear whether this exercise-induced protective effect is maintained when the heart is challenged with the β 1 -adrenergic receptor agonist dobutamine (DOB), which mimics acute exercise stress. Fischer 344 rats were randomly assigned to sedentary (SED) or voluntary wheel running (WR) groups for 10 weeks. At week 11, rats were treated with either 15 mg/kg DOX or saline. Five days later, ex vivo cardiac function was assessed using an isolated working heart model at baseline, during the infusion of 7.5 μg·kg -1 ·min -1 DOB, and during recovery. DOB infusion significantly increased left ventricular developed pressure (LVDP), maximal (dP/dt max ) and minimal (dP/dt min ) rate of left ventricular pressure development, and heart rate in all groups ( P < 0.05). SED + DOX also showed a lower baseline and recovery LVDP than WR + DOX (83 ± 12 vs. 109 ± 6 mm Hg baseline, 76 ± 11 vs. 100 ± 10 mm Hg recovery, P < 0.05). WR + DOX showed higher dP/dt max and lower dP/dt min when compared with SED + DOX during DOB infusion (7311 ± 1481 vs. 5167 ± 1436 mm Hg/s and -4059 ± 1114 vs.-3158 ± 1176 mm Hg/s, respectively). SED + DOX dP/dt max was significantly lower during baseline and during recovery when compared with all other groups ( P < 0.05). These data suggest that exercise preconditioning preserved cardiac function after DOX exposure even when the heart is challenged with DOB, and it appeared to preserve the heart's ability to recover from this functional challenge.

Instantaneous Right Ventricular to Pulmonary Artery Systolic Pressure Difference in Cardiac Surgery: A Retrospective and Prospective Cohort Study

BackgroundDuring cardiac surgery, right ventricular outflow tract obstruction (RVOTO) is defined as an instantaneous pressure difference ≥ 6 mm Hg between right ventricular systolic pressure (RVSP) and pulmonary artery systolic pressure (PASP), for ≥ 5 minutes. Risk factors for RVOTO remain poorly understood. This cohort study was designed to evaluate the incidence, characteristics, and outcomes of the patients who experienced RVOTO. MethodsInstantaneous pressure difference between RVSP and PASP was measured by means of a pulmonary artery catheter with a right ventricular port during cardiac surgery from a retrospective (n = 295) and a prospective (n = 105) cohort. ResultsFrom the retrospective and prospective cohorts, respectively, incidence of RVOTO was 30.2% and 36.2% before cardiopulmonary bypass (CPB) initiation and 43.7% and 47.6% after CPB separation. Before CPB initiation, patients with RVOTO had higher cardiac output (4.2 ± 1.5 vs 3.8 ± 1.1 L/min; P = 0.033) and received more inhaled epoprostenol (79% vs 61%; P = 0.005) and inotropes (66% vs 51%; P = 0.016) compared with those without RVOTO. After CPB separation, patients with RVOTO had higher heart rate (62 ± 15 vs 58 ± 13 beats/min; P = 0.011), cardiac output (4.1 ± 1.4 vs 3.7 ± 1.1 L/min; P = 0.003), and CPB duration (90 ± 45 vs 77 ± 30 min, P = 0.014), had lower fluid balance (758 ± 1123 vs 1063 ± 1089 mL; P = 0.021), and were more exposed to intratracheal milrinone (12% vs 4%; P = 0.015) compared with those without RVOTO. The time with persistent organ dysfunction (TPOD) at 28 days after surgery was similar among patients who had an RVOTO event, before CPB initiation or after CPB separation, compared with those who did not. ConclusionsRVOTO is common in cardiac surgery. However, it is not associated with longer TPOD.

Cardioprotective effect of chelidonic acid against doxorubicin-induced cardiac toxicity in rats

Introduction and objectivesThe current study evaluates the effect of chelidonic acid on doxorubicin-induced cardiac toxicity. Chelidonic acid (CA) is a natural pyran-skeleton heterocyclic compound found in rhizomes of the perennial plant, celandine (Chelidonium majus). MethodsWistar rats were given an intraperitoneal injection of doxorubicin (1.25 mg/kg, cumulative dose of 20 mg/kg) four times per week for a duration of four weeks to induce cardiotoxicity. CA treatment (10, 20, and 40 mg/kg orally for four weeks) was started together with doxorubicin. ResultsCA treatment reduced myocardial damage and improved cardiac dysfunction in doxorubicin-treated rats. It improved blood pressure, restored ST wave height and normalized the QTc interval compared to the rats treated only with doxorubicin. Administration of CA for four weeks reduced left ventricular end-diastolic pressure. Moreover, CA treatment decreased the level of cardiac markers such as creatine kinase-myocardial band (CK-MB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and cardiac troponin-T. Masson's trichrome, hematoxylin, and eosin staining of heart tissue revealed that CA attenuated the deleterious effects of doxorubicin and prevented further damage and fibrosis in rats. ConclusionThe study findings confirm that CA treatment can protect the myocardium against doxorubicin-induced cardiotoxicity.

Impact of Right Ventricular Pressure Overload on Myocardial Stiffness Assessed by Natural Wave Imaging.

Right ventricular (RV) hemodynamic performance determines the prognosis of patients with RV pressure overload. Using ultrafast ultrasound, natural wave velocity (NWV) induced by cardiac valve closure was proposed as a new surrogate to quantify myocardial stiffness. This study aimed to assess RV NWV in rodent models and children with RV pressure overload vs control subjects and to correlate NWV with RV hemodynamic parameters. Six-week-old rats were randomized to pulmonary artery banding (n=6), Sugen hypoxia-induced pulmonary arterial hypertension (n=7), or sham (n=6) groups. They underwent natural wave imaging, echocardiography, and hemodynamic assessment at baseline and 6weeks postoperatively. The authors analyzed NWV after tricuspid and after pulmonary valve closure (TVC and PVC, respectively). Conductance catheters were used to generate pressure-volume loops. In parallel, the authors prospectively recruited 14 children (7 RV pressure overload; 7 age-matched control subjects) and compared RV NWV with echocardiographic and invasive hemodynamic parameters. NWV significantly increased in RV pressure overload rat models (4.99 ± 0.27m/s after TVC and 5.03 ± 0.32m/s after PVC in pulmonary artery banding at 6weeks; 4.89 ± 0.26m/s after TVC and 4.84 ± 0.30m/s after PVC in Sugen hypoxia at 6weeks) compared with control subjects (2.83 ± 0.15m/s after TVC and 2.72 ± 0.34m/s after PVC). NWV after TVC correlated with both systolic and diastolic parameters including RV dP/dtmax (r=0.75; P< 0.005) and RV Ees (r=0.81; P< 0.005). NWV after PVC correlated with both diastolic and systolic parameters and notably with RV end-diastolic pressure (r=0.65; P< 0.01). In children, NWV after both right valves closure in RV pressure overload were higher than in healthy volunteers (P< 0.01). NWV after PVC correlated with RV E/E' (r=0.81; P=0.008) and with RV chamber stiffness (r=0.97; P=0.03). Both RV early-systolic and early-diastolic myocardial stiffness show significant increase in response to pressure overload. Based on physiology and our observations, early-systolic myocardial stiffness may reflect contractility, whereas early-diastolic myocardial stiffness might be indicative of diastolic function.

Impact of bridging veno-venous extracorporeal membrane oxygenation to COVID-19 lung transplantation.

Veno-venous extracorporeal membrane oxygenation (VV-ECMO) therapy is being increasingly used as respiratory support for patients with severe coronavirus disease 2019 (COVID-19)-associated acute respiratory distress syndrome (ARDS). However, the long-term outcome of VV-ECMO as a bridge to lung transplantation in COVID-19-associated ARDS remains unclear, hence the purpose of this study aimed to evaluate its long-term outcome, safety, and feasibility. This was a retrospective cohort study from an institutional lung transplantation database between June 2020 and June 2022. Data on demographics, pre-transplantation laboratory values, postoperative outcomes, preoperative and postoperative transthoracic echocardiography findings, and survival rates were collected. Chi-square, Mann-Whitney U, Student's t, Kaplan-Meier, and Wilcoxon signed-rank tests were used for analysis. Twenty-five patients with COVID-19-associated ARDS underwent lung transplant surgery with VV-ECMO bridge. Unfortunately, six patients with COVID-19-associated ARDS using VV-ECMO died while waiting for transplantation during the same study period. Patients with VV-ECMO bridge were a more severe cohort than 16 patients without VV-ECMO bridge (lung allocation score: 88.1 vs. 74.9, P<0.001). These patients had longer intensive care unit and hospital stays (P=0.03 and P=0.02, respectively) and a higher incidence of complications after lung transplantation. The one-year survival rate of patients with VV-ECMO bridge was lower than that of patients without (78.3% vs. 100.0%, P=0.06), but comparable to that of patients with other lung transplant indications (84.2%, P=0.95). Echocardiography showed a decrease in the right ventricular systolic pressure (P=0.01), confirming that lung transplantation improved right heart function. Our findings suggest that VV-ECMO can be used to safely bridge patients with COVID-19 associated ARDS with right heart failure.

Correlation of left atrial strain with invasively measured left ventricular end-diastolic pressure; determining LA strain cut-off value.

Left atrium longitudinal strain (LAS) with speckle tracking method has been proposed as a non-invasive method for the assessment of left ventricular filling pressure and diastolic dysfunction. This study aimed to investigate left atrial strain compared to invasively measured left ventricular filling pressure. All Patients candidates for coronary angiography were consecutively recruited. LAS measured by transthoracic echocardiography. Left ventricular end-diastolic pressure (LVEDP) pressure was invasively measured. Current echocardiographic modalities for diastolic function evaluated. A total of 125 people were included. 45 patients had preserved ejection fraction (EF ≥ 50%) and 85 patients had reduced EF (EF < 50%) and compared two groups. LVEDP was significantly higher in reduced EF compared to preserved EF (p-value < 0.001). LA-reservoir and LA-booster strains were significantly lower in patients with reduced EF compared to preserved EF (p-value = 0.008, mean Reservoir = 16.4% ± 6.4, mean Reservoir = 19.5% ± 5.6, respectively) and (p-value = 0.009, mean Booster = 9.09% ± 4.0, mean Booster =11. 9% ± 4.3, respectively). LA 4ch-reservoir strain <14.4%, and LA 2ch-reservoir strain <14.1% were related to LVEDP≥20 mmHg (sensitivity 63.5% and specificity 75%) (sensitivity 77.9% and specificity of 60%) respectively. LAS is significantly lower in patients with elevated LVEDP (≥ 20mmHg). LAS is significantly lower in patients with reduced EF. Both LA-reservoir and LA-booster strains have a significant relation to predicting LVFP but LA-reservoir strain is more accurate. The mean LA-reservoir strain less than 12.4% is associated with LVEDP ≥ 20mmHg.

Cardiac remodelling during pregnancy in women with congenital heart disease and systemic left ventricle.

Women with congenital heart disease (CHD) are at risk of pregnancy-related adverse outcomes (PRAO). The purpose of this study was to assess temporal changes in cardiac structure and function (cardiac remodelling) during pregnancy, and the association with PRAO in women with CHD. Retrospective study of pregnant women with CHD and serial echocardiograms (2003-2021). Cardiac structure and function were assessed at pre-specified time points: prepregnancy, early pregnancy, late pregnancy, and postnatal period. PRAO was defined as the composite of maternal cardiovascular, obstetric, and neonatal complications. The study comprised 81 women with CHD (age, 29 ± 5 years). Compared to the baseline echocardiogram, there was a relative increase in right ventricular systolic pressure (RVSP) (relative change 13 ± 5%, P < 0.001, in early pregnancy; and 18 ± 5%, P < 0.001, in late pregnancy). There was a relative decrease in right ventricle free wall strain (RVFWS) (relative change -11 ± 3%, P < 0.001, in late pregnancy; and -11 ± 4%, P = 0.003, in postnatal period), and a relative decrease in RVFWS/RVSP (relative change, -10 ± 5%, P = 0.02 in early pregnancy, -26 ± 7%, P < 0.001, in late pregnancy, and -14 ± 5%, P < 0.001, in postnatal period). Baseline right ventricular to pulmonary arterial (RV-PA) coupling, and temporal change in RV-PA coupling were associated with PRAO, after adjustment for maternal age and severity of cardiovascular disease. Women with CHD had a temporal decrease in RV systolic function and RV-PA coupling, and these changes were associated with PRAO. Further studies are required to delineate the aetiology of deterioration in RV-PA coupling during pregnancy, and the long-term implications of right heart dysfunction observed in the postnatal period.

MicroRNA-210 mediates hypoxia-induced pulmonary hypertension by targeting mitochondrial bioenergetics and mtROS flux.

Chronic hypoxia is a common cause of pulmonary hypertension (PH). We test the hypothesis that microRNA-210 (miR-210) mediates hypoxia-induced PH by targeting mitochondrial metabolism and increasing reactive oxygen species (mtROS) production in the lungs. Adult wildtype (WT) or miR-210 knockout (KO) mice were exposed to hypoxia (10.5% O2) or normoxia for 4 weeks. We measured miR-210 levels, right ventricular systolic pressure (RVSP), and histological changes in heart and lung tissues. Mitochondrial bioenergetics and mtROS production were assessed in isolated lung mitochondria. Hypoxia increased right ventricular wall thickness and pulmonary vessel wall muscularization in WT, but not miR-210 KO mice. No sex differences were observed. In male mice, hypoxia increased miR-210 levels in the lung and RVSP, which were abrogated by miR-210 deficiency. Hypoxia upregulated mitochondrial oxygen consumption rate and mtROS flux, which were negated in miR-210 KO animals. In addition, chronic hypoxia increased macrophage accumulation in lungs of WT, but not miR-210 KO mice. Moreover, miR-210 overexpression in lungs of WT animals recapitulated the effects of hypoxia and increased mitochondrial oxygen consumption rate, mtROS flux, right ventricular wall thickness, pulmonary vessel wall muscularization and RVSP. MitoQ revoked the effects of miR-210 on lung mitochondrial bioenergetics, right ventricular and pulmonary vessel remodeling and RVSP. Our findings with loss-of-function and gain-of-function approaches provide explicit evidence that miR-210 mediates hypoxia-induced PH by upregulating mitochondrial bioenergetics and mtROS production in a murine model, revealing new insights into the mechanisms and therapeutic targets for treatment of PH.

Detection of contractility changes in the heart from arterial blood pressure data using symmetric Projection Attractor Reconstruction

The potential for unintended drug induced changes in cardiac contractility is a major concern in medicines development. Whilst direct left ventricular pressure (LVP) measurement is the gold standard for measuring cardiac contractility in vivo, it is resource intensive and poses a welfare burden on research animals. In contrast, arterial blood pressure (BP) measurement has fewer challenges. Symmetric Projection Attractor Reconstruction (SPAR) is a signal processing technique which transforms physiological time-series signals into a corresponding visual image (‘attractor’), amplifying morphology changes within physiological waveforms. It was hypothesized that SPAR analysis of BP signals would provide a surrogate measure of cardiac contractility by specifically amplifying the maximum slope of the systolic upstroke. BP (abdominal aorta) signals obtained from beagle dogs, treated with positive and negative inotropes, were retrospectively analysed to identify signal features that correlated with the maximum upslope of the LVP signal from simultaneously acquired LVP recordings. SPAR transformation of BP signals quantified drug induced changes in the maximum slope of the systolic upstroke. We identified key SPAR metrics that provided >0.8 correlation with the LVP maximum upslope, outperforming the BP systolic upstroke alone. This was observed for all 4 different drugs, doses and time points evaluated across studies. Thus, we conclude that the SPAR measures derived from the BP signal could be used as a first pass in vivo screen to flag any risk of drug induced changes in cardiac contractility during the conduct of non-clinical medicines development, potentially reducing or replacing the need to perform direct left ventricular measurements.

Complex Pulmonary Artery Rehabilitation in Children with Alagille Syndrome: An Early Single-Center Experience of a Successful Collaborative Work.

Objective: In this paper, we share our single-center experience of successful multidisciplinary management of patients with Alagille syndrome. In addition, we aim to highlight the need for an Alagille program for effectively managing these patients, in general, and particularly peripheral pulmonary artery stenosis associated with this syndrome. Study Design: This is a retrospective review of six children with Alagille syndrome and advanced liver involvement who underwent pulmonary artery reconstruction between 2021 and 2022. Cardiac diagnosis, co-existing liver disease burdens, management approach, and short-term outcomes were analyzed. Results: All the patients underwent one-stage extensive bilateral branch pulmonary rehabilitation. Concomitant procedures included repair of tetralogy of Fallot in one patient and repair of supravalvar pulmonary artery stenosis in two. One patient had balloon pulmonary branch angioplasty before surgery. In all patients, there was a decrease in right ventricular systolic pressure post-operatively. Three patients underwent liver transplantation for pre-existing liver dysfunction. At a median 3-year follow-up, all the patients were alive with their right ventricular systolic pressure less than half of their systemic systolic pressure. One patient underwent balloon angioplasty due to new and recurrent left pulmonary artery stenosis 13 months after surgery. Conclusion: Pulmonary arteries can be successfully rehabilitated surgically in the presence of complex branch disease. Patients with advanced liver disease can undergo successful complex pulmonary artery reconstruction, which can facilitate their future liver transplantation course. A multidisciplinary team approach is a key for successful management of Alagille patients.

Proportion of sleep-related breathing disorders and their association with echocardiographic parameters in stable patients with chronic obstructive pulmonary disease: a cross-sectional observational exploratory study

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality throughout the world. The coexistence of COPD and obstructive sleep apnea (OSA) (i.e., overlap syndrome) has been reported in several studies. Both disorders independently increase the risk of cardiovascular complications. Hence, there is a theoretical possibility that cardiovascular parameters may be worse in patients with overlap syndrome compared to those with only COPD. However, this has been sparsely assessed in the literature. This study aimed to compare the clinical characteristics, echocardiography, and sleep parameters amongst COPD patients with and without sleep-related breathing disorders (SRBD). This observational, cross-sectional study included 30 patients with stable COPD. All participants underwent a detailed clinical evaluation, followed by level 1 polysomnography (PSG). Each participant underwent echocardiographic evaluation to estimate mean pulmonary artery pressure from right ventricular systolic pressure (RVSP). Based on their PSG findings, participants were classified into non-SRBD and SRBD groups. Both groups were further compared with respect to clinical characteristics, echocardiographic, and PSG parameters. We found that most of the participants (93.3%) were male, and the mean age of the study population was 56±8.2 years. The only SRBD identified in this study was OSA, which was observed in 80% of participants. In this group, OSA was not associated with obesity. Systemic hypertension (50%) was the most common comorbidity, followed by diabetes mellitus (26.67%), but both were not significantly different between the groups. The mean RVSP was significantly higher amongst OSA patients than non-OSA patients (41.25±14.98 versus 30.83±5.84, respectively; p=0.01). OSA was seen in 80% of participants with stable COPD, even in the absence of obesity. The presence of OSA was associated with a higher RVSP in this patient group.

Immune cell profiling of the ICAM1 p.K56M heart failure with preserved ejection fraction risk variant.

Intercellular adhesion molecule-1 (ICAM-1) facilitates inflammation via leucocyte recruitment and has been implicated in heart failure with preserved ejection fraction (HFpEF). Approximately 35% of African American individuals carry a copy of an ICAM1 missense variant (rs5491; p.K56M), which is associated with an increased risk of HFpEF. The pathways by which rs5491 increases HFpEF risk are not well defined. We evaluated the circulating immune cell profile of rs5491. Among African American individuals in the Multi-Ethnic Study of Atherosclerosis, we evaluated the associations of rs5491 with 29 circulating peripheral blood mononuclear cell subsets. The top immune cells were then related to echocardiographic measures of structure and function. Among 502 individuals with immune cell profiling (mean age 63years, 51% female), 191 individuals (38%) had at least one copy of rs5491. Each additional rs5491 allele was significantly associated with higher proportions of Tc17 CD8+ cytotoxic T cells (β=1.34, SE=0.45, P=9.5×10-5) and Tc2 CD8+ cytotoxic T cells (β=1.19, SE=0.44, P=0.00012). There were no other associations noted between rs5491 and the remaining immune cells. A higher proportion of Tc17 cells was significantly associated with a higher left ventricular ejection fraction, E/e' average and right ventricular systolic pressure (RVSP), while a higher proportion of Tc2 cells was significantly associated with a higher RVSP. The ICAM1 p.K56M variant (rs5491) carries a distinct and inflammatory T-cell subset profile. These cytotoxic T cells are in turn associated with alterations in cardiac function and adverse haemodynamics later in life, thus providing insight into pathways by which rs5491 may increase the risk of HFpEF.

Pulmonary Flow Management by Combination Therapy of Hemostatic Clipping and Balloon Angioplasty for Right Ventricular-Pulmonary Artery Shunt in Hypoplastic Left Heart Syndrome.

Controlling pulmonary blood flow in patients who have undergone Norwood palliation, especially early postoperatively, is challenging due to a change in the balance of systemic and pulmonary vascular resistance. We applied a combination therapy of clipping and balloon angioplasty for right ventricle-pulmonary artery (RV-PA) shunt to control pulmonary blood flow, but the influence of the combination therapy on the PA condition is uncertain. Retrospectively analysis was conducted of all infants with hypoplastic left heart syndrome who had undergone Norwood palliation with RV-PA shunt at Okayama University Hospital from January 2008 to September 2022. A total of 50 consecutive patients underwent Norwood palliation with RV-PA shunt in this study period. Of them, 29 patients underwent RV-PA shunt flow clipping, and the remaining 21 had unclipped RV-PA shunt. Twenty-three patients underwent balloon angioplasty for RV-PA shunt with clips. After balloon angioplasty, oxygen saturation significantly increased from 69 (59-76)% to 80 (72-86)% (p < 0.001), and the narrowest portion of the clipped conduit significantly improved from 2.8 (1.8-3.4) to 3.8 (2.9-4.6) mm (p < 0.001). In cardiac catheterizations prior to Bidirectional cavo-pulmonary shunt (BCPS), there were no significant differences in pulmonary-to-systemic flow ratio (Qp/Qs), ventricular end-diastolic pressure, Nakata index, arterial saturation, mean pulmonary artery pressure and pulmonary vascular resistance index. On the other hand, in Cardiac catheterizations prior to Fontan, Nakata index was larger in the clipped group (p = 0.02). There was no statistically significant difference in the 5-year survival between the two groups (clipped group 96%, unclipped group 74%, log-rank test: p = 0.13). At least, our combination therapy of clipping and balloon angioplasty for RV-PA shunt did not negatively impact PA growth. Although there is a trend toward better but not statistically significant difference in outcomes in the clipped group compared to the non-clipped group, this treatment strategy may play an important role in improving outcomes in hypoplastic left heart syndrome.

Pulmonary artery banding for cardiomyopathy in young children: First trial in China.

Heritable dilated cardiomyopathy (DCM) or DCM associated with congenital or acquired left ventricular diseases carries a significant mortality risk. Pulmonary artery banding (PAB) has been proposed as an alternative to heart transplantation. This study aimed to delineate the clinical development, ventricular reverse remodelling, and functional regeneration of the dilated left ventricle, presenting as a pioneering approach in China. This prospective study was initiated in November 2021, involving paediatric patients with a significant dilated left ventricle and preserved right ventricle who underwent surgical PAB. The baseline characteristics and clinical information during follow-up were collected. Seven patients (five boys) with a median age of 240 (148, 1028) days have been included thus far. No procedural or follow-up mortality was observed. The modified Ross functional class improved from treatment to follow-up of 348 (200, 629) days, and the median left ventricular ejection fraction increased from 27.0 (15.0, 34.0) % before surgery to 61.0 (52.0, 68.0) % (P<0.05); the median left ventricular end-diastolic diameter and corresponding Z-scores decreased from 43.0 (40.0, 55.0) mm [+9.4 (+7.7, +11.7)] to 33.0 (29.0, 39.0) mm [+1.8 (+1.3, +3.8)] (P<0.05). Functional regeneration of the left ventricle was observed in five patients. Three of them underwent balloon dilation of the PAB to relieve excessively elevated right ventricular pressures. The application of PAB should adhere to strict criteria. Initial results are promising for infants and even toddlers with a dilated left ventricle and limited probability of spontaneous recovery. PAB can be an alternative when there is a shortage of donor transplants and assist devices, especially for low- and middle-income countries.

Active decompression during automated head-up cardiopulmonary resuscitation

BackgroundThe combination of active compression-decompression cardiopulmonary resuscitation (ACD-CPR) with an impedance threshold device (ITD) and controlled head-up positioning (AHUP-CPR) is associated with improved outcomes compared with conventional CPR (C-CPR). This study focused on the role of active decompression (AD) during AHUP-CPR. MethodsFarm pigs (n = 10, ∼40 kg) were anesthetized, intubated and ventilated. Physiological parameters and right ventricular pressure–volume loops were recorded continuously. Ventricular fibrillation was induced and left untreated for 10 mins, followed by automated C-CPR (2 min), ACD + ITD CPR in the flat position (2 min), and then AHUP-CPR with 3 cm of lift above the neutral chest position. After 15 min of CPR, AD was discontinued and then restarted incrementally to 4 cm. Data were analyzed with a linear mixed-effects model, using random intercepts for individual pigs. ResultsUpon cessation of AD during AHUP-CPR, decompression right atrial pressure (+59%) increased (p < 0.01), whereas multiple hemodynamic parameters positively associated with perfusion, including coronary (−25%) and cerebral perfusion pressures (−11%), end-tidal CO2 (−13%), stroke volume and cardiac output (−26%), decreased immediately and significantly with p < 0.05. Restoration of AD reduced right atrial pressure and increased positive perfusion parameters in an incremental manner. Only with ≥ 3 cm of AD were all hemodynamic parameters restored to ≥ 90% of pre-AD discontinuation levels. ConclusionFull chest wall lift, achieved with ≥ 3 cm of AD, was needed to maintain and optimize hemodynamics during AHUP-CPR in pigs. These findings should be considered when optimizing care with this new approach.

Exercise Intolerance Is Associated with Cardiovascular Dysfunction in Long COVID-19 Syndrome.

Background/Objectives: Cardiorespiratory complications are commonly reported among patients with long COVID-19 syndrome. However, their effects on exercise capacity remain inconclusive. We investigated the impact of long COVID-19 on exercise tolerance combining cardiopulmonary exercise testing (CPET) with resting echocardiographic data. Methods: Forty-two patients (55 ± 13 years), 149 ± 92 days post-hospital discharge, and ten healthy age-matched participants underwent resting echocardiography and an incremental CPET to the limit of tolerance. Left ventricular global longitudinal strain (LV-GLS) and the left ventricular ejection fraction (LVEF) were calculated to assess left ventricular systolic function. The E/e' ratio was estimated as a surrogate of left ventricular end-diastolic filling pressures. Tricuspid annular systolic velocity (SRV) was used to assess right ventricular systolic performance. Through tricuspid regurgitation velocity and inferior vena cava diameter, end-respiratory variations in systolic pulmonary artery pressure (PASP) were estimated. Peak work rate (WRpeak) and peak oxygen uptake (VO2peak) were measured via a ramp incremental symptom-limited CPET. Results: Compared to healthy participants, patients had a significantly (p < 0.05) lower LVEF (59 ± 4% versus 49 ± 5%) and greater left ventricular end-diastolic diameter (48 ± 2 versus 54 ± 5 cm). In patients, there was a significant association of E/e' with WRpeak (r = -0.325) and VO2peak (r = -0.341). SRV was significantly associated with WRpeak (r = 0.432) and VO2peak (r = 0.556). LV-GLS and PASP were significantly correlated with VO2peak (r = -0.358 and r = -0.345, respectively). Conclusions: In patients with long COVID-19 syndrome, exercise intolerance is associated with left ventricular diastolic performance, left ventricular end-diastolic pressure, PASP and SRV. These findings highlight the interrelationship of exercise intolerance with left and right ventricular performance in long COVID-19 syndrome.