Time Constant Of Isovolumic Relaxation Research Articles

Hypoxia-Induced Myocardial Hypertrophy Companies with Apoptosis Enhancement and p38-MAPK Pathway Activation.

Li, Xiaoxu, Zhijun Pu, Gang Xu, Yidong Yang, Yu Cui, Xiaoying Zhou, Chenyuan Wang, Zhifeng Zhong, Simin Zhou, Jun Yin, Fabo Shan, Chengzhong Yang, Li Jiao, Dewei Chen, and Jian Huang. Hypoxia-induced myocardial hypertrophy companies with apoptosis enhancement and p38-MAPK pathway activation. High Alt Med Biol. 25:186-196, 2024. Background: Right ventricular function and remodeling are closely associated with symptom severity and patient survival in hypoxic pulmonary hypertension. However, the detailed molecular mechanisms underlying hypoxia-induced myocardial hypertrophy remain unclear. Methods: In Sprague-Dawley rats, hemodynamics were assessed under both normoxia and hypobaric hypoxia at intervals of 7 (H7), 14 (H14), and 28 (H28) days. Morphological changes in myocardial tissue were examined using hematoxylin and eosin (HE) staining, while myocardial hypertrophy was evaluated with wheat germ agglutinin (WGA) staining. Apoptosis was determined through TUNEL assays. To further understand the mechanism of myocardial hypertrophy, RNA sequencing was conducted, with findings validated via Western blot analysis. Results: The study demonstrated increased hypoxic pulmonary hypertension and improved right ventricular diastolic and systolic function in the rat models. Significant elevations in pulmonary arterial systolic pressure (PASP), mean pulmonary arterial pressure (mPAP), right ventricular mean pressure (RVMP), and the absolute value of +dp/dtmax were observed in the H14 and H28 groups compared with controls. In addition, right ventricular systolic pressure (RVSP), -dp/dtmax, and the mean dp/dt during isovolumetric relaxation period were notably higher in the H28 group. Heart rate increased in the H14 group, whereas the time constant of right ventricular isovolumic relaxation (tau) was reduced in both H14 and H28 groups. Both the right heart hypertrophy index and the heart weight/body weight ratio (HW/BW) were elevated in the H14 and H28 groups. Myocardial cell cross-sectional area also increased, as shown by HE and WGA staining. Western blot results revealed upregulated HIF-1α levels and enhanced HIF-2α expression in the H7 group. In addition, phosphorylation of p38 and c-fos was augmented in the H28 group. The H28 group showed elevated levels of Cytochrome C (Cyto C), whereas the H14 and H28 groups exhibited increased levels of Cleaved Caspase-3 and the Bax/Bcl-2 ratio. TUNEL analysis revealed a rise in apoptosis with the extension of hypoxia duration in the right ventricle. Conclusions: The study established a link between apoptosis and p38-MAPK pathway activation in hypoxia-induced myocardial hypertrophy, suggesting their significant roles in this pathological process.

The Action and Mechanism of Trehalose on GATA4 Autophagy Degradation and Ventricular Remodeling.

To probe the effect of trehalose on myocardial hypertrophy and its specific molecular mechanism. C57BL/6J male mice were divided into four subgroups: Sham operation subgroup (Sham), negative sham subgroup (Sham+Trehalose), transverse aortic constriction (TAC), and trehalose treatment subgroup (TAC+Trehalose). Immediately after the TAC operation, trehalose at a dose of 10 mg/kg was given daily via gavage. After four weeks, changes in cardiac function were evaluated using ultrasound to measure EF (ejection fraction), FS (fractional shortening), IVRT (isovolumic relaxation time), MPI (myocardial performance index), Tau (isovolumic relaxation time constant), LVESP (left ventricular end-systolic pressure), and EDPVR (end-diastolic pressure-volume relationship). The profiles of autophagy-associated proteins (p62, LC3II/I, and Beclin-1) and GATA4 protein in mice myocardial tissues were assessed by Western blotting (WB). Myocardial cells were classified from TAC mice into five groups: Control, Trehalose, Phenylephrine (PE), PE+Trehalose, and PE+Trehalose+autophagy inhibitor chloroquine groups. In the PE group, cardiomyocytes were treated with 50 μmol/L PE. Then, the cells were treated with trehalose (100 μmol/L), trehalose (100 μmol/L)+autophagy (20 μmol/L) for 24 hours respectively. The Control group was treated with the same amount of normal saline. Flow cytometry was utilized to detect myocardial cell apoptosis in each subgroup. The alterations in apoptosis and autophagy-correlated proteins (p62, LC3II/I, and Beclin-1) were assessed by WB. Additionally, the level of GATA4 protein upstream of autophagy was estimated. Furthermore, the expression levels of pro-apoptotic proteins Bad, BAX, Cleaved-caspase-3, and anti-apoptotic protein Bcl-2 were examined by WB. The TAC operation significantly augmented myocardial hypertrophy, heart weight-to-body weight ratio, and myocardial cell apoptosis in mice (p < 0.05). Trehalose significantly improved cardiac hypertrophy, cardiomyocyte apoptosis, and cardiac function decline in mice. Additionally, it also significantly enhanced autophagy in mouse cardiac tissues (p < 0.05). At the cellular level, trehalose significantly decreased PE-elicited apoptosis and promoted the protein expressions of Beclin-1 and LC3 II/I in cardiomyocytes while significantly dampening the profiles of p62 and GATA4 in cells. The effect of trehalose and chloroquine treatment was significantly greater than that of the trehalose group. Trehalose significantly abates myocardial hypertrophy and pressure overload-induced cardiomyocyte apoptosis in mice. The cardioprotective effect of trehalose on enhanced autophagy is attributed, at least in part, to the promotion of autophagic degradation of GATA4.

Dysregulated ACE/Ang II/Ang1-7 signaling provokes cardiovascular and inflammatory sequelae of endotoxemia in weaning preeclamptic rats

Weaning preeclamptic (PE) rats exhibit exaggerated endotoxic signs of hypotension and cardiac autonomic neuropathy. Considering the role of renin-angiotensin system (RAS) in maternal programming during PE, we investigated the hypothesis that gestational modulation of offensive (Angiotensin II, Ang II) and defensive (Ang 1–7) components of RAS alleviates cardiovascular hyperresponsiveness of weaning PE mothers to postpartum endotoxemia. PE was induced by treating pregnant rats with the nitric oxide synthase inhibitor L-NAME (50 mg/kg/day) for 7 consecutive days starting from gestational day 14. The PE-associated elevations in gestational systolic blood pressure and proteinuria were reduced after gestational treatment with Ang 1–7 (Ang II-derived vasodilator), losartan (AT1 receptor antagonist), pioglitazone (RAS modulator), or combined losartan/pioglitazone, with the latter therapy being the most effective. In weaning PE rats, the potentiated falls in mean arterial pressure and spectral index of cardiac sympathovagal balance (low frequency/high frequency ratio) caused by i.v. Lipopolysaccharides (LPS, 5 mg/kg) were attenuated by all therapies. Pioglitazone and Ang 1–7 were more effective in reversing increases and decreases in left ventricular contractility and isovolumic relaxation time constant, respectively, seen in endotoxic PE mothers. Immunohistochemically, cardiac Toll-like receptor 4 (TLR-4) expression was increased in endotoxic PE rats, and this effect was abrogated by Ang 1–7 or losartan/pioglitazone. The same treatments blunted the increased cardiac angiotensin converting enzyme (ACE) expression whereas ACE2 expression was altered by none of the intervening therapies. Overall, the mitigation of Ang II/ACE imbalances alleviates the sensitized cardiovascular and inflammatory actions of endotoxemia in weaning PE mothers.

Understanding Complex Interactions in Pediatric Diastolic Function Assessment

Diagnosing left ventricular diastolic dysfunction (DD) noninvasively in children is difficult as no validated pediatric diagnostic algorithm is available. The aim of this study is to explore the use of machine learning to develop a model that uses echocardiographic measurements to explain patterns in invasively measured markers of DD in children. Children at risk for developing DD were enrolled, including patients with Kawasaki disease, heart transplantation, aortic stenosis, and coarctation of the aorta when undergoing clinical left heart catheterization. Simultaneous invasive pressure measurements were made using a high-fidelity catheter (time constant of isovolumic relaxation [Tau, τ], left ventricular end-diastolic pressure, and maximum negative rate of pressure change) and echocardiographic DD measurements. Spearman correlations were performed for each echocardiographic feature with invasive markers to understand pairwise relationships. Separate random forest (RF) models were implemented to assess all echocardiographic features, key demographic data, and clinical diagnosis in predicting invasive markers. A backward stepwise regression model was simultaneously implemented as a comparative conventional reference model. The relative importance of all parameters was ranked in terms of accuracy reduction. Model approximation was then performed using a regression tree with the top-ranked features of each RF model to improve model interpretability. Regression coefficients of the linear models were presented. Fifty-nine children were included. Spearman correlations were generally low. The RF models' performance measures were noninferior to those of the linear model. However, the linear model's regression coefficients were unintuitive. The highest ranked important features for the RF models were propagation velocity for Tau, E/propagation velocity ratio for left ventricular end-diastolic pressure, and systolic global longitudinal strain rate for maximum negative rate of pressure change. Estimating individual components of DD can potentially improve the noninvasive assessment of pediatric DD. Although pairwise correlations measured were weak and linear regression coefficients unintuitive,approximated machine learning models aided in understanding how echocardiographic and invasive parameters of DD are related. This machine learning approach could help in further development of pediatric-specific diagnostic algorithms.

Abstract 10386: Supervised Machine Learning for Relating Echocardiographic Parameters to Invasive Pressure Measurements in Pediatric Diastolic Function Assessment

Introduction: Diagnosing diastolic dysfunction (DD) non-invasively in children is challenging as no validated pediatric diagnostic algorithm is available. The aim of this study is to use machine learning (ML) to identify a model that integrates echocardiographic measurements to predict invasive hemodynamic markers of DD in children. Methods: We enrolled children with Kawasaki disease, heart transplant, aortic stenosis, and coarctation of the aorta undergoing left heart catheterization. We obtained simultaneous invasive and echo DD measurements. We applied random forest (RF) algorithms to develop separate models for each cath marker (time constant of isovolumic relaxation (Tau), LVEDP, and -dP/dt max) and used demographics, diagnosis, and echo features as inputs. Model approximation was done using a regression tree with the top ranked features of each RF model to improve model interpretability (Figure 1). Spearman correlations were also assessed. Results: 59 children were included. Spearman correlations were low. However, the RF models' adjusted R 2 values in predicting Tau, LVEDP, and -dP/dt max are 0.62, 0.51, and 0.83, respectively. A representative ML-generated tree for LVEDP is shown in Figure 2. The most important features were propagation velocity (Vp) for Tau; E/Vp ratio for LVEDP; and systolic global longitudinal strain rate for -dP/dt max. Model approximation showed that a Vp &lt; 42 cm/s predicted a Tau &gt; 39 ms, and an E/Vp &gt; 2.4 predicted an LVEDP &gt; 13 mmHg. Conclusions: Predicting invasively measured diastolic parameters with echo data may be improved using ML algorithms. Model approximation may help better interpret the complex interactions in ML models.

Growth hormone-releasing hormone agonists ameliorate chronic kidney disease-induced heart failure with preserved ejection fraction

Therapies for heart failure with preserved ejection fraction (HFpEF) are lacking. Growth hormone-releasing hormone agonists (GHRH-As) have salutary effects in ischemic and nonischemic heart failure animal models. Accordingly, we hypothesized that GHRH-A treatment ameliorates chronic kidney disease (CKD)-induced HFpEF in a large-animal model. Female Yorkshire pigs (n = 16) underwent 5/6 nephrectomy via renal artery embolization and 12 wk later were randomized to receive daily subcutaneous injections of GHRH-A (MR-409; n = 8; 30 µg/kg) or placebo (n = 8) for 4 to 6 wk. Renal and cardiac structure and function were serially assessed postembolization. Animals with 5/6 nephrectomy exhibited CKD (elevated blood urea nitrogen [BUN] and creatinine) and faithfully recapitulated the hemodynamic features of HFpEF. HFpEF was demonstrated at 12 wk by maintenance of ejection fraction associated with increased left ventricular mass, relative wall thickness, end-diastolic pressure (EDP), end-diastolic pressure/end-diastolic volume (EDP/EDV) ratio, and tau, the time constant of isovolumic diastolic relaxation. After 4 to 6 wk of treatment, the GHRH-A group exhibited normalization of EDP (P = 0.03), reduced EDP/EDV ratio (P = 0.018), and a reduction in myocardial pro-brain natriuretic peptide protein abundance. GHRH-A increased cardiomyocyte [Ca2+] transient amplitude (P = 0.009). Improvement of the diastolic function was also evidenced by increased abundance of titin isoforms and their ratio (P = 0.0022). GHRH-A exerted a beneficial effect on diastolic function in a CKD large-animal model as demonstrated by improving hemodynamic, structural, and molecular characteristics of HFpEF. These findings have important therapeutic implications for the HFpEF syndrome.

Abstract 13577: Human Induced Pluripotent Stem Cell-derived Cardiomyocyte Patches Ameliorate Right Ventricular Diastolic Dysfunction in a Rat Pressure-overloaded Right Heart Model

Introduction: Right ventricular (RV) failure following definitive repair of congenital heart diseases (CHD) have great impact on survival after surgical intervention. Recently, human induced pluripotent stem cell-derived cardiomyocyte (hiPS-CM) sheet transplantation ameliorated left ventricular dysfunction in preclinical study, associating possible efficacy in RV failure of CHD. Hypothesis: We hypothesized whether hiPS-CM patch could improve distressed RV function in rat pressure overload model. Methods: F344/NJcl- rnu/rnu rat (7-9 weeks old, male, 180-210g) underwent pulmonary artery banding (PAB) via left thoracotomy under general anesthesia. Four weeks after PAB, hiPS-CM patch transplantation to the RV was performed in the hiPS-CM patch transplantation group (n = 10), whereas a sham operation was performed in the sham group (n =10). We evaluated for cardiac catheterization (CATH) data and pathological findings 8 weeks after PAB. Results: In CATH, RV end diastolic pressure (sham; 10.0 ± 4.1 vs hiPS-CM; 5.5 ± 2.7 mmHg, P &lt; 0.01), time constant of isovolumic relaxation (sham; 24.9 ± 8.6 vs hiPS-CM; 16.5 ± 6.4 ms, P &lt; 0.01) and end-diastolic pressure volume-relation (sham; 365.6 ± 246.3 vs hiPS-CM; 214.0 ± 147.4 mmHg/mL, P &lt;0.05) were significantly ameliorated in hiPS-CM group compared with sham group. Sirius-red staining showed a significant anti-fibrotic effects in the hiPS-CM group compared with the sham group (13.4 ± 5.3 vs 20.7 ± 4.8 %, P &lt;0.05). Factor VIII stain showed that myocardial capillary vascular density in the hiPS-CM group was significantly higher than in the sham group (640 ± 131 vs 362 ± 31 units/mm 2 , P &lt;0.001). hiPS-CMs were detectable on epicardium 2 weeks after hiPS-CM patch transplantation. The expression levels of vascular endothelial growth factor and hepatocyte growth factor in the hiPS-CM group was significantly higher than in the sham group (P &lt;0.05). Conclusions: In a rat model of a pressure-overload RV, hiPS-CM patch transplantation improved the diastolic function with suppressed ventricular fibrosis and increased capillary density, suggesting a promising treatment for RV failure in CHD patients after surgical repair.

The Relationship Between Heart Rate and Left Ventricular Isovolumic Relaxation During Normoxia and Hypoxia-Asphyxia in Newborn Piglets.

Background: Many asphyxiated neonates have cardiac complications including arrhythmia and contractile dysfunction. Little is known about the relationship between heart rate (HR) and diastolic function in asphyxiated neonates. We aimed to study the relationship between HR and left ventricular (LV) isovolumic relaxation (IVR) in neonates with asphyxia using a swine model.Methods: Term newborn piglets were anesthetized and acutely instrumented with the placement of Millar® catheter in the left ventricle. Hemodynamic parameters including HR, cardiac output, stroke volume, dP/dtmax and dP/dtmin, and IVR time constant (Tau) were continuously measured and recorded. Sixteen piglets were exposed to 50-minute normocapnic hypoxia followed by asphyxia (mean of 3.2 min) by clamping of the endotracheal tube. Sham-operated piglets (n = 11) had no hypoxia nor asphyxia. The relationship between HR and other hemodynamic parameters were analyzed using Pearson Product Moment correlation test.Results: Asphyxiated piglets had cardiogenic shock and metabolic acidosis (vs. sham-operated piglets). There were significant correlations between HR and diastolic function as shown by Tau at baseline (sham-operated: r = -0.68, p = 0.02; asphyxia: r = -0.55, p = 0.03) and during normoxia (53 min) of sham-operated piglets (r = -0.69, p = 0.02). HR and Tau was not correlated during hypoxia-asphyxia (HA) (r = -0.01, p = 0.97). Cardiac output was tightly correlated with stroke volume (p < 0.001) but not HR throughout the experimental period in both groups. There was no significant correlation between HR and other hemodynamic parameters during the experimental period in both groups.Conclusion: We observed an uncoupling between HR and IVR Tau of the neonatal heart during HA, which deserves further studies of the relationship between HR and LV diastolic function.

A Reduction in Cardiac Function Precedes Structural Adaptations in Experimental Spinal Cord Injury

IntroductionChronic high‐thoracic spinal cord injury (SCI) is associated with systolic dysfunction, cardiomyocyte atrophy and the upregulation of major proteolytic pathways in the heart. How such dysfunction manifests with time is presently unknown.MethodsMale Wistar rats underwent complete SCI at the 3rd thoracic spinal level (T3‐SCI; n=10) or dorsal durotomy (SHAM; n=5). T3‐SCI rats were terminated at different time points: three days post‐SCI (3‐day SCI; n=5) or seven days post‐SCI (7‐day SCI; n=5). SHAM rats were terminated at seven days post‐durotomy. On termination day, prior to euthanasia, left‐ventricular (LV) catheterization was performed to assess cardiac function. Additionally, cardiac tissue was collected for histological analysis to quantify cardiomyocyte dimensions (standardized to femur length).ResultsRelative to SHAM, T3‐SCI rats at both 3‐day and 7‐day post‐SCI exhibited reduced stroke work (SW; p=0.036), load‐independent contractile function (inferred with end‐systolic pressure‐volume relationship, ESPVR; p=0.0013) and maximal rate of LV systolic pressure increment (dP/dtmax; p=0.0070). The maximal rate of LV relaxation (i.e. ‐dP/dtmin; p=0.019) was reduced at 3‐day and 7‐day post‐SCI vs. SHAM; however, tau (time constant of isovolumic relaxation) was not different (p=0.15). There were no differences for any functional indices between 3‐day vs. 7‐day SCI. Histological analysis of cardiomyocytes indicates no significant differences in length and width in SCI groups vs. SHAM (length p=0.20; width p=0.24).ConclusionSystolic cardiac function decreased significantly in both 3‐day and 7‐day SCI rats vs. SHAM. This indicates a rapid onset of cardiac dysfunction following T3‐SCI. Cardiomyocyte atrophy was not present in either 3‐day or 7‐day SCI rats, implying a reduction in cardiac function precedes structural remodeling.Support or Funding InformationHeart and Stroke Foundation of Canada (HSFC), International Collaboration on Repair Discoveries (ICORD) and Blusson Integrated Cure Partnership (BICP).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Longer Ischemic Time is Associated with Increased Ventricular Stiffness as Measured by Pressure-Volume Loop Analysis in Pediatric Heart Transplant Recipients.

The purpose of this study was to investigate the associations between clinical factors and cardiac function as measured by pressure-volume loops (PVLs) in a pediatric heart transplant cohort. Patients (age<20years) who underwent heart transplantation presenting for a clinically indicated catheterization were enrolled. PVLs were recorded using microconductance catheters (CD Leycom®, Zoetermeer, Netherlands). Demographic data, serum B-type natriuretic peptide (BNP), time from transplant, ischemic time, presence of transplant coronary artery disease, donor-specific antibodies, and history of rejection were recorded at the time of catheterization. PVL data included contractility indices: end-systolic elastance and preload recruitable stroke work; ventricular-arterial coupling index; ventricular stiffness constant, Beta; and isovolumic relaxation time constant, tau. Associations between PVL measures and clinical data were investigated using non-parametric statistical tests. A total of 18 patients were enrolled. Median age was 8.7years (IQR 5-14years). There were ten males and eight females. Six patients had a history of rejection and ten had positive donor-specific antibodies. There was no transplant coronary artery disease. Median BNP was 100pg/mL (IQR 46-140). Time from transplant to PVL obtained during catheterization procedure was 4.1years (IQR 1.7-7.8year). No single clinical characteristic was statistically significant when correlated with PVL data. However, longer ischemic time was associated with worse Beta (r=0.49, p=0.05). Our study found that longer ischemic times are associated with increased left ventricular stiffness. No other single clinical variable is associated with cardiac dysfunction as determined by PVL analysis.

Abstract 12046: ARFI Ultrasound Elastography Measures Isovolumic Relaxation Time Constant for Assessment of Diastolic Function

Introduction: Diastolic dysfunction is a leading cause of morbidity and mortality in heart failure. Assessment of diastolic function has been a challenging topic for many decades. One index of diastolic function is the isovolumic relaxation time constant (τ). This measurement is not used routinely in the clinic because it requires a left ventricular (LV) pressure catheter. Other noninvasive methods provide correlates of the time constant but do not measure the actual value. It has been shown recently that ultrasound elastography (Acoustic Radiation Force Impulse Imaging (ARFI)) can provide a temporal stiffness measurement of the myocardium during the cardiac cycle. The clinical value of the ARFI measured time course of softening has not been shown. Hypothesis: We assessed the hypothesis that ARFI Elastography can be used to measure the isovolumic relaxation time constant of the LV. Methods: This study was performed in eight isolated rabbit hearts in working mode. A pressure catheter was used to record the LV pressure simultaneously with ARFI. LV free wall ARFI measurements were recorded using an ultrasound probe. In order to extend the range of τ (tau) measurements, 3 of the subjects were subjected to ischemia (total of 11 measurements from 8 subjects). Results: Tau measured by ARFI was linearly related to the τ measurement derived from LV pressure with the slope of 0.92 and R 2 = 0.90 indicating the near equivalence of the values. Mean ± SEM of τ derived from pressure and ARFI were 33.7 ± 6.4 ms and 34.8 ± 6.2 ms respectively. Conclusions: ARFI ultrasound elastography can be used to measure the relaxation time constant of the left ventricle. This is the first time that τ has been measured directly using an ultrasound technique. ARFI measurements have the benefits of ultrasound imaging including noninvasiveness, cost efficiency and portability. Translation of this technique to transthoracic imaging in humans would provide an important screening measure of diastolic function.

Speckle-Tracking Echocardiographic Measures of Right Ventricular Diastolic Function Correlate with Reference Standard Measures Before and After Preload Alteration in Children.

The accuracy of echocardiographic measures of right ventricular (RV) diastolic function has been sparsely studied. Our objective was to evaluate the correlation between echocardiographic and reference standard measures of RV diastolic function derived from micromanometer pressure analysis before and after preload alteration in children. Echocardiograms and micromanometer pressure analyses were prospectively performed before and after fluid bolus in children undergoing right heart catheterization. The isovolumic relaxation time constant (τ) and end-diastolic pressure (EDP) were measured. Conventional and speckle-tracking echocardiographic (STE) parameters of RV systolic and diastolic function were assessed. Normal saline bolus was given to increase RV EDP by 20%. Twenty-eight studies were performed in 22 patients with congenital heart disease or postheart transplantation. Mean age was 8.7±6.1years. RV longitudinal early diastolic strain rate (EDSR) correlated with τ before (r=0.57, p=0.001) and after fluid bolus (r=0.48, p=0.008). No conventional echocardiographic measures correlated with τ both before and after fluid bolus. Multiple regression analysis revealed RV EDSR and LV circumferential EDSR as independent predictors of RV τ. There were no independent predictors of EDP. RV EDSR appears to correlate with the reference standard measure of early active ventricular relaxation in children at baseline and after changes in preload. Conventional echocardiographic measures of diastolic function were not predictive of diastolic function after preload alteration. Future studies should assess the prognostic significance of STE measures of diastolic function in this population.

Abstract 10878: Validation of Non-invasive Measures of Diastolic Function in Children: A Simultaneous Echocardiography and Conductance Catheterization Study

Introduction: The accuracy of echocardiography in evaluating left ventricular (LV) diastolic function has not been validated in children. The objective of this study was to compare echocardiographic and gold-standard measures of LV diastolic function in children. Methods: Patients undergoing routine left heart catheterization were prospectively enrolled. Pressure-volume loops (PVL) were obtained via conductance catheters. The end-diastolic pressure-volume relationship was obtained via balloon occlusion of the vena cavae. PVL measures of diastolic function were divided into early active relaxation (the isovolumic relaxation time constant, tau), and ventricular stiffness (the chamber stiffness constant, β). End-diastolic pressure (EDP) was also recorded. Echocardiographic measures of diastolic function were derived from spectral Doppler, tissue Doppler, and 2D speckle-tracking. The relationships between PVL and echocardiographic measures were determined using Spearman’s correlation. Results: Of 24 patients, 18 patients were s/p heart transplant, 5 patients had a small patent ductus arteriosus or coronary fistula. Mean age was 9.1 ± 5.6 years. The median τ was 24.9 ms (IQR 22.8 - 28.4 ms), median β was 0.094 (IQR 0.035 - 0.154), and median EDP was 9 mmHg (IQR 8 - 13 mmHg). Statistically significant correlations between invasive and echocardiographic measures of diastolic function are reported in the Table. No echocardiographic measures correlated with β. Conclusion: Early diastolic echocardiographic measures correlate with tau and may accurately represent early active relaxation in children. Modest associations exist between echocardiographic measures and EDP. The use of these non-invasive measures in accurately assessing LV diastolic function appears promising in children. However, no echocardiographic measures correlate with chamber stiffness. The development of such measures merits further study.

Afterload-induced diastolic dysfunction contributes to high filling pressures in experimental heart failure with preserved ejection fraction

Myocardial stiffness and upward-shifted end-diastolic pressure-volume (P-V) relationship (EDPVR) are the key to high filling pressures in heart failure with preserved ejection fraction (HFpEF). Nevertheless, many patients may remain asymptomatic unless hemodynamic stress is imposed on the myocardium. Whether delayed relaxation induced by pressure challenge may contribute to high end-diastolic pressure (EDP) remains unsettled. Our aim was to assess the effect of suddenly imposed isovolumic afterload on relaxation and EDP, exploiting a highly controlled P-V experimental evaluation setup in the ZSF1 obese rat (ZSF1 Ob) model of HFpEF. Twenty-week-old ZSF1 Ob (n = 12), healthy Wistar-Kyoto rats (WKY, n = 11), and hypertensive ZSF1 lean control rats (ZSF1 Ln, n = 10) underwent open-thorax left ventricular (LV) P-V hemodynamic evaluation under anesthesia with sevoflurane. EDPVR was obtained by inferior vena cava occlusions to assess LV ED chamber stiffness constant β, and single-beat isovolumic afterload acquisitions were obtained by swift occlusions of the ascending aorta. ZSF1 Ob showed increased ED stiffness, delayed relaxation, as assessed by time constant of isovolumic relaxation (τ), and elevated EDP with normal ejection fraction. Isovolumic afterload increased EDP without concomitant changes in ED volume or heart rate. In isovolumic beats, relaxation was delayed to the extent that time for complete relaxation as predicted by 3.5 × monoexponentially derived τ (τexp) exceeded effective filling time. EDP elevation correlated with reduced time available to relax, which was the only independent predictor of EDP rise in multiple linear regression. Our results suggest that delayed relaxation during pressure challenge is an important contributor to lung congestion and effort intolerance in HFpEF.

Heart Rate–Dependent Left Ventricular Diastolic Function in Patients With and Without Heart Failure

BackgroundChronic heart rate (HR) reduction in the treatment of heart failure (HF) with systolic dysfunction is beneficial, but the immediate mechanical advantages or disadvantages of altering HR are incompletely understood. We examined the effects of increasing HR on early and late diastole in humans with and without HF. Methods and ResultsWe studied force-interval relationships of the left ventricle (LV) in 11 HF patients and 14 control subjects. HR was controlled by right atrial pacing, and LV pressure was recorded by a micromanometer-tipped catheter. The time constant of isovolumic relaxation (tau) was calculated, and simultaneous sonographic images were analyzed for LV volumes. The end-diastolic pressure-volume relationship (EDPVR) was analyzed with the use of a single-beat method. Tau was shortened in response to increasing HR in both groups; the slope of this relationship was steeper in HF than in control subjects. The predicted volume at a theoretic pressure of 0 mm Hg (V30) increased at higher HRs compared with baseline, shifting the predicted EDPVR compliance curve to the right in HF patients but not in control subjects. ConclusionsIn HF, changes in HR affect early relaxation and diastolic compliance to a greater extent than in control subjects. Our study reinforces current recommendations for HR-lowering drug treatment in HF.

IL-18 neutralization during alveolar hypoxia improves left ventricular diastolic function in mice.

In patients, an association exists between pulmonary diseases and diastolic dysfunction of the left ventricle (LV). We have previously shown that alveolar hypoxia in mice induces LV diastolic dysfunction and that mice exposed to hypoxia have increased levels of circulating interleukin-18 (IL-18), suggesting involvement of IL-18 in development of diastolic dysfunction. IL-18 binding protein (IL-18BP) is a natural inhibitor of IL-18. In this study, we hypothesized that neutralization of IL-18 during alveolar hypoxia would improve LV diastolic function. Mice were exposed to 10% oxygen for 2 weeks while treated with IL-18BP or vehicle. Cardiac function and morphology were measured using echocardiography, intraventricular pressure measurements and magnetic resonance imaging (MRI). For characterization of molecular changes in the heart, both real-time PCR and Western blotting were performed. ELISA technique was used to measure levels of circulating cytokines. As expected, exposure to hypoxia-induced LV diastolic dysfunction, as shown by prolonged time constant of isovolumic relaxation (τ). Improved relaxation with IL-18BP treatment was demonstrated by a significant reduction towards control τ values. Decreased levels of phosphorylated phospholamban (P-PLB) in hypoxia, but normalization by IL-18BP treatment suggest a role for IL-18 in regulation of calcium-handling proteins in hypoxia-induced diastolic dysfunction. In addition, MRI showed less increase in right ventricular (RV) wall thickness in IL-18BP-treated animals exposed to hypoxia, indicating an effect on RV hypertrophy. Neutralization of IL-18 during alveolar hypoxia improves LV diastolic function and partly prevents RV hypertrophy.

Left Ventricular Function by Pressure‐Volume Loop Analysis before and after Percutaneous Repair of Large Atrial Septal Defects

The intent of the present study was to evaluate changes in ventricular function with percutaneous closure of atrial septal defect (ASD), as it is associated with alterations in ventricular loading and function. Transcatheter occlusion of ASD imparts acute changes in volume loading of the left ventricle (LV) that obscures measurement of ventricular function by load-dependent indices. To differentiate between changes in ventricular loading and function, load-independent indices of ventricular function must be utilized. During transcatheter occlusion of ASD, subjects underwent measurement of LV pressure and volume by the conductance catheter method. Load-dependent indices of ventricular function included: systolic and diastolic pressures, +dP/dtmax , and -dP/dtmax . Load-independent indices included: elastance and tau, the preload-independent time constant ofisovolumic relaxation. To obtain elastance, afterload was augmented by phenylephrine bolus pre- and post-device occlusion. In total, 29 patients (age 2-79 years) underwent ASD device occlusion (device size 12-38 mm, median 28 mm). Load-dependent indices were obtained in all, and satisfactory pressure-volume loops in 11. At baseline, LV end-diastolic pressure was 5-23 mmHg (13 ± 5 mmHg) and tau was 31 ± 6 ms. Postclosure of the ASD, LV systolic and diastolic pressures rose by 10 ± 11 mmHg and 5 ± 3 mmHg, respectively (P < 0.05), and +dP/dtmax rose from 1,288 ± 313 mmHg/sec to 1,415 ± 465 mmHg/sec (P < 0.05), but -dP/dtmax was unchanged. Elastance significantly improved (9.4 ± 8.3 mmHg/mL vs. 13.0 ± 7.3 mmHg/mL, P < 0.05) and tau was unchanged. Transcatheter occlusion of ASD is associated with acute improvement in load-independent indices of systolic function in this cohort, without significant worsening of the preload-independent index of diastolic function.

Comparison of Pressure–Volume Loop and Echocardiographic Measures of Diastolic Function in Patients With a Single-Ventricle Physiology

Echocardiographic measurements of diastolic function have not been validated against invasive pressure-volume loop (PVL) analysis in the single-ventricle population. The authors hypothesized that echocardiographic measures of diastolic function would correlate with PVL indices of diastolic function in patients with a single-ventricle physiology. The conductance-derived PVL measures of diastolic function included the isovolumic relaxation time constant (τ), the maximum rate of ventricular pressure decline (peak -dP/dt), and a measure of passive diastolic stiffness (μ). The echocardiographic measures included Doppler inflow patterns of the dominant atrioventricular valve (DAVV), tissue Doppler velocities (TDI) at the lateral (ventricular free wall) component of the DAVV annulus, and the TDI-derived isovolumic relaxation time (IVRT'). The correlation between PVL and echocardiographic measures was examined. The study enrolled 13 patients at various stages of surgical palliation. The median age of the patients was 3 years (range 3 months to 19 years). τ correlated well with Doppler E:A (r = 0.832; p = 0.005), lateral E:E' (r = 0.747; p = 0.033), and IVRT' (r = 0.831; p = 0.001). Peak -dP/dt also was correlated with IVRT' (r = 0.609; p = 0.036), and μ also was correlated with IVRT' (r = 0.884; p = 0.001). This study represents the first-ever comparison of diastolic echocardiographic and PVL indices in a single-ventricle population. The findings show that Doppler E:A, lateral E:E', and IVRT' correlate well with PVL measures of diastolic function. This study supports further validation of echocardiographic measures of diastolic function versus PVL measures of diastolic function in the single-ventricle population.

Ethanol‐evoked reduction in myocardial contractility and autonomic dysregulation in freely moving female rats

Acute ethanol reduces blood pressure (BP) in proestrus female rats via reduction in cardiac output, which reflected reduced cardiac contractility based on indirectly measured dP/dtmax (maximal rise of ventricular pressure over time). In this study we directly measured cardiac contractility indices [left ventricular developed pressure (LVDP), dP/dtmax and the ventricular isovolumic relaxation time constant (Tau)] in conscious freely moving female rats via fluid filled catheter. We validated this technique using isoproterenol, which produced the expected dose‐related increases in dP/dtmax. To test whether ethanol cardiac depressant effect precedes the hypotensive response in freely moving female rats, we directly measured cardiac function along with BP, HR, in two animal groups received either intragastric ethanol (1 g/kg) or water (control). Further, we conducted offline analysis of sympathovagal activity (spectral analysis) to elucidate ethanol effect on autonomic balance. Acute ethanol, compared to water, caused slowly developing reduction in BP that was significant at 40 min, reached its nadir at 70 min, and lasted till the experiment ended at 90 min. However, significant reductions in myocardial contractility indices (LVDP and dP/dtmax) started 10 min after ethanol, which preceded the hypotensive response. The high‐frequency (HFα) component of spectral analysis of RRI (cardiac vagal control) increased by intragastric ethanol starting at 20 min and continued throughout the experiment. However, the spectral measure of sympathetic activity, low‐frequency (LFα) component of RRI, was not affected by ethanol resulting in net decreases in the sympathovagal, LFRRI/HFRRI, ratio. Collectively, our findings directly implicate the reduction in cardiac contractility and enhancement of cardiac vagal control, at least partly, in acute ethanol‐evoked hypotensive effect in proestrus female rats.Supported by NIAAA Grant 2R01 AA14441–06

Heart failure with preserved ejection fraction: chronic low-intensity interval exercise training preserves myocardial O2 balance and diastolic function

We have previously reported chronic low-intensity interval exercise training attenuates fibrosis, impaired cardiac mitochondrial function, and coronary vascular dysfunction in miniature swine with left ventricular (LV) hypertrophy (Emter CA, Baines CP. Am J Physiol Heart Circ Physiol 299: H1348-H1356, 2010; Emter CA, et al. Am J Physiol Heart Circ Physiol 301: H1687-H1694, 2011). The purpose of this study was to test two hypotheses: 1) chronic low-intensity interval training preserves normal myocardial oxygen supply/demand balance; and 2) training-dependent attenuation of LV fibrotic remodeling improves diastolic function in aortic-banded sedentary, exercise-trained (HF-TR), and control sedentary male Yucatan miniature swine displaying symptoms of heart failure with preserved ejection fraction. Pressure-volume loops, coronary blood flow, and two-dimensional speckle tracking ultrasound were utilized in vivo under conditions of increasing peripheral mean arterial pressure and β-adrenergic stimulation 6 mo postsurgery to evaluate cardiac function. Normal diastolic function in HF-TR animals was characterized by prevention of increased time constant of isovolumic relaxation, normal LV untwisting rate, and enhanced apical circumferential and radial strain rate. Reduced fibrosis, normal matrix metalloproteinase-2 and tissue inhibitors of metalloproteinase-4 mRNA expression, and increased collagen III isoform mRNA levels (P < 0.05) accompanied improved diastolic function following chronic training. Exercise-dependent improvements in coronary blood flow for a given myocardial oxygen consumption (P < 0.05) and cardiac efficiency (stroke work to myocardial oxygen consumption, P < 0.05) were associated with preserved contractile reserve. LV hypertrophy in HF-TR animals was associated with increased activation of Akt and preservation of activated JNK/SAPK. In conclusion, chronic low-intensity interval exercise training attenuates diastolic impairment by promoting compliant extracellular matrix fibrotic components and preserving extracellular matrix regulatory mechanisms, preserves myocardial oxygen balance, and promotes a physiological molecular hypertrophic signaling phenotype in a large animal model resembling heart failure with preserved ejection fraction.