Left Ventricular Diastolic Compliance Research Articles

Brief Repetitive Pressure Overload Elicits a Fibrosis-Independent Reduction in Left Ventricular Diastolic Compliance in Swine

Objective: We have previously shown that swine subjected to repetitive pressure overload (RPO) via daily 2-hr infusions of phenylephrine (PE) develop a reduction in left ventricular (LV) diastolic compliance that coincides with increased interstitial myocardial fibrosis. The objective of the present study was to determine if brief episodes of RPO produce a similar cardiac phenotype. Methods: Swine (n=6) were subjected to a single 30-min PE infusion (300 μg/min) to determine if brief pressure overload causes myocardial injury (circulating cardiac troponin I; cTnI), inflammation (IL-6), and cardiac dysfunction (echocardiography). A separate group of swine (n=5) were subsequently instrumented with an indwelling venous catheter to enable daily 30-min PE infusions for 2 weeks (“Brief RPO”). LV diastolic compliance (ΔLVEDV/ΔLVEDP during PE) and interstitial fibrosis (picrosirius red staining) were compared to values derived from swine subjected to prolonged RPO (2-hr PE/day; n=8) and age-matched controls (n=8). Results: A single episode of brief pressure overload led to an increase in circulating cTnI (from 22±6 ng/L at baseline to 365±12 ng/L 3-hours post-PE) and IL-6 (from 10±2 to 34±4 pg/mL), along with a transient reduction in LV ejection fraction (from 65±2 to 45±5 %, all p<0.05). Brief RPO led to a significant reduction in LV diastolic compliance (ΔLVEDV/ΔLVEDP: 0.59±0.13 mL/mmHg vs. 1.87±0.12 mL/mmHg in controls; p<0.01) that was nearly identical to that observed after prolonged RPO (0.58±0.17 mL/mmHg, p=0.95). Surprisingly, in contrast to prolonged RPO (10.0±1.4% collagen) the brief RPO-induced reduction in LV compliance was not accompanied by an increase in interstitial fibrosis (5.0±0.3 % collagen vs. 5.0±0.3 % collagen in controls, p=0.95). Conclusion: Brief pressure overload initially causes myocardial injury and inflammation, with repetitive exposure leading to a reduction in LV compliance that is similar to that observed following prolonged RPO. However, the brief RPO-induced reduction in LV compliance occurs in the absence of fibrosis, suggesting that mechanisms of repetitive stretch-induced myocardial stiffening may depend on the duration of episodic pressure overload. Supported by funding from the U.S. Department of Veterans Affairs and National Institutes of Health. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Acute and chronic effects of levosimendan in the ZSF1 obese rat model of heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is a syndrome characterized by impaired cardiovascular reserve in which therapeutic options are scarce. Our aim was to evaluate the inodilator levosimendan in the ZSF1 obese rat model of HFpEF. Twenty-week-old male Wistar-Kyoto (WKY), ZSF1 lean (ZSF1 Ln) and ZSF1 obese rats chronically treated for 6-weeks with either levosimendan (1 mg/kg/day, ZSF1 Ob + Levo) or vehicle (ZSF1 Ob + Veh) underwent peak-effort testing, pressure-volume (PV) haemodynamic evaluation and echocardiography (n = 7 each). Samples were collected for histology and western blotting. In obese rats, skinned and intact left ventricular (LV) cardiomyocytes underwent in vitro functional evaluation. Seven additional ZSF1 obese rats underwent PV evaluation to assess acute levosimendan effects (10 μg/kg + 0.1 μg/kg/min). ZSF1 Ob + Veh presented all hallmarks of HFpEF, namely effort intolerance, elevated end-diastolic pressures and reduced diastolic compliance as well as increased LV mass and left atrial area, cardiomyocyte hypertrophy and increased interstitial fibrosis. Levosimendan decreased systemic arterial pressures, raised cardiac index, and enhanced LV relaxation and diastolic compliance in both acute and chronic experiments. ZSF1 Ob + Levo showed pronounced attenuation of hypertrophy and interstitial fibrosis alongside increased effort tolerance (endured workload raised 38 %) and maximum O2 consumption. Skinned cardiomyocytes from ZSF 1 Ob + Levo showed a downward shift in sarcomere length-passive tension relationship and intact cardiomyocytes showed decreased diastolic Ca2+ levels and enhanced Ca2+ sensitivity. On molecular grounds, levosimendan enhanced phosphorylation of phospholamban and mammalian target of rapamycin. The observed effects encourage future clinical trials with levosimendan in a broad population of HFpEF patients.

Short- and long-term treatment with mineralocorticoid receptor antagonist improved heart failure with preserved ejection fraction in obese female mice with or without ovariectomy-induced post-menopausal condition

Obesity and metabolic syndrome are major risks for the development of heart failure with preserved ejection fraction (HFpEF), especially in women after menopause. Although mineralocorticoid receptor antagonists (MRAs) improve outcomes of HF with reduced EF, their beneficial effects on HFpEF remain to be established. We aimed to characterize the potential beneficial effects of an MRA treatment on HFpEF related to obesity in post-menopausal condition or not. After 12 weeks of a high fat diet (HFD), B6D2 female mice underwent an ovariectomy (OVX) followed by an MRA treatment (daily gavage) for a short- or long-term (1 or 12 weeks). The metabolic profile of the mice was analyzed by glucose and insulin tolerance tests. Echocardiography and hemodynamics measurements were performed to evaluate the left ventricular (LV) function. LV coronary perfusion and reserve were measured by MRI, and exercise capacity was evaluated on a treadmill. LV and adrenal gland remodeling were explored by histology and immunohistochemistry. After 12 weeks of HFD, the LV systolic fractional shortening, stroke volume and cardiac output in obese mice were not different to control mice. However, impairment of the LV diastolic compliance was significantly improved either by a short- or long-term MRA treatment (LV-End-Diastolic-Pressure-Volume-Relation, mmHG/RVU: CTL 1.00 ± 0.27, HFD 3.29 ± 0.56, HFD + OVX 7.33 ± 0.35; P < 0.01 vs. CTL; HFD + MRAshort 1.13 ± 0.35, HFD + OVX + MRAshort 0.95 ± 0.51; P < 0.01 vs. untreated). Furthermore, the long-term MRA treatment ameliorated glucose and insulin tolerance tests and reduced LV interstitial fibrosis (Fibrosis, %: CTL 7.03 ± 0.41, HFD 8.82 ± 0.36, HFD + OVX 9.80 ± 0.58; P < 0.01 vs. CTL; HFD + MRA 6.45 ± 0.51, HFD + OVX + MRA 8.26 ± 0.28; P < 0.01 vs. untreated). Moreover, in HFD + OVX mice, the long-term MRA treatment increased the coronary perfusion reserve as well as the running distance during the treadmill stress test. Obesity and post-menopausal condition affected adrenal gland organization with capsule thinning in all obese mice, spindles cortical extensions in the HFD group, cortical dysplasia and disorganized vascular network in the HFD + OVX group. Overall, our data demonstrate that both short- and long-term MRA treatment improved diastolic dysfunction in pre- and post-menopausal obese female mice with HFpEF.

1143 IMPACT OF NON-CARDIAC COMORBIDITIES ON DIASTOLIC PROPERTIES IN HFREF AND HFMREF PATIENTS

Abstract Background and purpose The impact of non-cardiac comorbidities on left ventricular (LV) diastolic properties in HFrEF and HFmrEF patients is still uncertain. Aim of the study was to determine how comorbidities affect LV relaxation and diastolic compliance in patients with HFrEF and HFmrEF. Methods Consecutive patients diagnosed with HFrEF or HFmrEF were enrolled. Non-cardiac comorbidity were recorded: diabetes, chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), obstructive sleep apnea syndrome (OSAS), dyslipidemia and active or previous cancer. Patients underwent laboratory tests, including NT-pro-BNP. The following diastolic properties were evaluated non-invasively by echocardiography using previously validated methods: the time constant of isovolumetric relaxation (τ) and the diastolic stiffness index (β). Left atrial volume index (LAVi) was also recorded. Patients were divided in two groups: a) ≥2 comorbidities and b) &amp;lt;2 comorbidities. Results Seventy-five patients were enrolled of whom 73% reported dyslipidaemia, 26% diabetes, 20% CKD, 18% COPD, 8% cancer, 4% OSAS. Thirty-five patients (47%) presented with ≥2 comorbidities showing higher values of τ (62±15ms vs 48±15ms, p&amp;lt;0.001). Non- significant differences were found in β (6.12±0.3 vs 6.17±0.2; p= 0.582), left atrial volume index (47±34 vs 40±19, p= 0.386) and log-transformed NT-pro-BNP (6.2±1.4 vs 5.6±1.3; p= 0.323). Conclusion Among patients with HFrEF e HFmrEF the presence of multiple non-cardiac comorbidities was associated with more impaired proto-diastolic relaxation reflected by higher τ values. No significant differences were found in diastolic stiffness (β) and imaging and laboratory characteristics suggestive of increased end-diastolic LV filling pressure.

Abstract 15337: Chronic Oral Finerenone Treatment Does Not Improve Left Ventricular Diastolic Compliance in Swine With Repetitive Pressure Overload-Induced HFpEF

Introduction: The non-steroidal mineralocorticoid receptor antagonist finerenone has emerged as a potential treatment for heart failure with preserved ejection fraction (HFpEF) based, in part, on initial evidence of its anti-fibrotic properties. However, it is unclear whether chronic oral finerenone therapy can reverse established cardiac fibrosis. Accordingly, we tested the efficacy of chronic oral finerenone in a porcine model of HFpEF characterized by interstitial fibrosis and reduced left ventricular (LV) diastolic compliance in the absence of co-morbidities or anatomic LV hypertrophy. Methods: Swine (n=12) were subjected to daily (1 hr) episodes of repetitive LV pressure overload (RPO) for 2 weeks using phenylephrine (24 mg/hr) to transiently elevate LVEDP to ~30 mm Hg. After 2 weeks, RPO was discontinued and animals were followed for an additional 4 weeks, during which a subset received oral finerenone (20 mg/day; n=6). LV end-diastolic volume (EDV) and pressure (EDP) were measured at normal and elevated preload to assess LV compliance (ΔLVEDV/ΔLVEDP) and post-mortem picrosirius red staining was performed to quantify interstitial fibrosis vs. normal controls (n=8). Results: Four-weeks after cessation of RPO, untreated animals exhibited a significant increase in interstitial fibrosis vs. normal controls that was attenuated in finerenone-treated animals ( Figure A ). Despite this regression of interstitial collagen, a persistent reduction in LV diastolic compliance was observed after finerenone treatment (1.18 ± 0.33 mL/mmHg vs. 2.11 ± 0.22 mL/mmHg in normal controls; p=0.04) that was comparable to that of untreated animals after RPO (0.97 ± 0.22 mL/mmHg; p=0.61; Figure B ). Conclusion: Four weeks of chronic oral finerenone treatment does not restore LV diastolic compliance in swine with RPO-induced HFpEF despite regression of interstitial collagen content, suggesting that other factors may contribute to diastolic stiffening in this model.

C72 THE EFFECTS OF BATRIATIC SURGERY ON CARDIO–METABOLIC PROFILE AND CARDIAC REMODELING

Abstract Background Obesity is associated with cardiac remodeling resulting in hypertrophy of the left ventricle (LV) with a predominantly concentric pattern. LV remodeling and fibrosis induce mechanical and electrical dysfunction of the myocardial tissue, an increase in cardiac output, an increase of myocardial workload and mean arterial pressure. Objective To evaluate the impact of bariatric surgery, and therefore of anthropometric and cardio–metabolic variations, on cardiac structure and function. Methods Twenty–six obese patients treated with bariatric surgery were enrolled. All the patients at baseline and at 6 and 12 months underwent a complete anthropometrical evaluation, laboratory determinations and echocardiogram evaluation. The IR has been assessed by HOMA–IR. The patients were divided into two groups: the first group (8 patients) carried out a follow–up at 6 months post–surgery; the second group (18 patients) at 12 months post–surgery. Results As expected, an improvement in the anthropometric and metabolic profile in patients treated with bariatric surgery was observed. Echocardiographic data showed a significant increase in the Ejection Fraction (P &amp;lt; 0.001) and the E/A Ratio (P &amp;lt; 0.001) 6 months after bariatric surgery, a significant reduction in the Interventricular Septum thickness at 6 months (P &amp;lt; 0.001) and at 12 months (P &amp;lt; 0.002) post–surgery and a significant reduction in the Left Ventricular Mass at 6 months (P = 0.02) and at 12 months (P = 0.05) after bariatric surgery. A reduction no significant in the Left Ventricular posterior wall thickness has been observed. Conclusions Our data showed an increase of the systolic function, an increase of the left ventricular diastolic compliance and a reduction in subclinical cardiac organ damage. Therefore, significant weight loss obtained with bariatric surgery may lead to reverse cardiac remodeling, associated with beneficial effects on myocardial structure and systo-diastolic function.

Manipulation of Left Ventricular Loading Conditions is Necessary to Identify Diastolic Dysfunction in Swine with Repetitive Pressure Overload‐Induced HFpEF

ObjectiveDiagnosis of heart failure with preserved ejection fraction (HFpEF) is often complicated by the fact that many patients exhibit normal left ventricular (LV) mechanics at rest with a reduction in diastolic compliance that is only revealed when loading conditions are altered (e.g., during exercise stress). In an effort to identify parameters of diastolic function that could be utilized to detect alterations in compliance without manipulation of LV loading conditions, we utilized invasive hemodynamic analysis and speckle‐tracking echocardiography (STE) to assess diastolic strain and stiffness in swine with repetitive pressure overload (RPO)‐induced HFpEF.MethodsSwine (n=13) were subjected to 2‐weeks of RPO via daily intravenous administration of phenylephrine (PE; 400 ug/min; 1 hour/day) through an indwelling jugular vein catheter. Indices of LV relaxation as well as LV minimum and end‐diastolic pressure were obtained invasively before and after RPO at rest and during transient PE‐induced alterations in loading conditions. STE (Vivid 9; GE) was also performed throughout a single cardiac cycle to collect circumferential diastolic strain data, which were used alongside echocardiography‐derived measurements of chamber radius and wall thickness as well as catheter‐derived measurements of LV pressure to calculate regional and global circumferential subendocardial diastolic stiffness before and after RPO.ResultsCompared with baseline measurements, 2‐weeks of RPO did not significantly increase the time constant of LV relaxation (Tau; Figure A) or decrease the rate of LV pressure change during isovolumic relaxation (dP/dtmin; Figure B). Circumferential subendocardial stiffness derived via STE across a single cardiac cycle at rest was also unaffected by RPO (Figure C), despite a significant reduction in diastolic compliance that was revealed by construction of two‐point end‐diastolic pressure‐volume curves (Figure D) after manipulation of loading conditions (Figure E). Interestingly, single‐cycle STE‐derived stiffness measurements made during acute pressure overload were also similar at baseline and after RPO due to persistent elevations in LV minimum diastolic pressure during PE infusion at both timepoints.ConclusionsAlthough reductions in LV diastolic compliance are evident after chronic RPO when loading conditions are manipulated, abnormalities in LV mechanics are not exhibited at rest even when STE is used to assess diastolic stiffness throughout a single cardiac cycle. These findings highlight the challenges associated with identification of myocardial stiffening at rest in patients with HFpEF and reinforce the importance of studying LV mechanics under variable loading conditions.

Interstitial Fibrosis in HFpEF Attenuates Diastolic Circumferential Strain and the Transcriptional Response to Left Ventricular Pressure Overload

Objective We previously demonstrated thattransient repetitive pressure overload (RPO) in swine leads to myocardial interstitial fibrosis and reduced diastolic left ventricular (LV) compliance. While this phenotype is similar to that found in some patients with heart failure with preserved ejection fraction (HFpEF), it occurs in the absence of anatomic LV hypertrophy, persistent hypertension, or comorbidities. The present study was designed to determine if reduced LV diastolic distensibility alters the acute transcriptional response to transient pressure overload. Methods A total of 21 swine were studied. Hemodynamic assessment, echocardiography, and blood sampling were performed before and after a 60 minute intravenous infusion of phenylephrine (PE; 300 μg/min) to elevate LV end-diastolic pressure (EDP) to ~30 mmHg. Myocardial RNA from control animals (n=7) was compared to tissue isolated 24 hours after a single episode of pressure overload (n=6) or after 14 days of RPO (n=8). We assessed LV diastolic strain and compliance via echocardiography and quantified interstitial fibrosis with picrosirius red staining. Genes previously demonstrated to be altered after pressure overload including natriuretic peptides (ANP and BNP), inflammatory mediators (CD68 and CCR2) and pro-fibrotic factors (LOXL2 and Fibronectin) were assessed with quantitative PCR and normalized to β2 microglobulin. Results Transient PE infusion increased LV EDP from 14 ± 1 to 30 ± 1 mmHg and systolic arterial pressure from 120 ± 6 to 205 ± 6 mmHg (both p<0.01). The hemodynamic response to PE was similar during a single episode of pressure overload and after 14 days of RPO. There was concentric LV remodeling (LV mass/EDV: 1.3 ± 0.1 vs. 1.1 ± 0.1 g/mL; p<0.05) without anatomic hypertrophy after RPO (LV mass/body mass: 2.4 ± 0.1 vs. 2.3 ± 0.1 g/kg; p=0.37), yet interstitial fibrosis increased from 6.6 ± 0.7% to 12.9 ± 1.8% (p<0.05) and LV diastolic compliance (∆EDV/∆EDP) decreased from 1.7 ± 0.2 to 0.6 ± 0.2 mL/mmHg (p<0.05). As a result, myocardial diastolic circumferential strain after RPO was markedly reduced in comparison to a single episode of pressure overload in the normal heart (1.5 ± 2.7% after RPO vs. 11.1 ± 3.0% in controls; p<0.05). The reduction in diastolic circumferential strain after RPO markedly attenuated the transcriptional response to acute pressure overload (Figure). In normal myocardium, transient pressure overload upregulated natriuretic peptides (ANP 26-fold and BNP 12-fold; both p<0.01), pro-inflammatory genes (CD68 2.3-fold and CCR2 4-fold; p=0.06), and pro-fibrotic genes (LOXL2 3.4-fold and fibronectin 3.9-fold; p<0.05). In contrast, the reduction in diastolic strain after RPO prevented any increase in gene expression despite a similar magnitude of transient pressure overload. Conclusions These results dissociate the effects of myocardial strain from systolic and end-diastolic pressure on the transcriptional response to LV pressure overload. The dependence of gene expression on diastolic strain rather than LV pressure may explain observations such as the frequent absence of natriuretic peptide elevation in patients with HFpEF.

Impaired Adenosine‐Mediated Coronary Vasodilation in Swine with Repetitive Pressure Overload‐Induced Heart Failure with Preserved Ejection Fraction

Objective We recently demonstrated that swine subjected to 2-weeks of intermittent repetitive pressure overload (RPO) develop cardiac phenotypic characteristics of heart failure with preserved ejection fraction (HFpEF), including a reduction in left ventricular (LV) diastolic compliance, myocyte hypertrophy, and interstitial fibrosis without an increase in LV mass. The objective of the present study was to determine if this pattern of myocardial remodeling is accompanied by alterations in coronary microvascular function or structure that contribute to an impaired vasodilator response to adenosine (ADO). Methods Regional myocardial blood flow (BF) was assessed via administration of fluorescent microspheres at rest and during ADO vasodilation in swine subjected to 2-weeks of RPO (300 µg/min phenylephrine (PE), 30 min/day; n=5) and normal controls (n=5). Adenosine (ADO)-mediated vasodilation was initially assessed at a submaximal dose (0.15 mg/kg/min), followed by a maximal vasodilating dose (0.90 mg/kg/min) with concomitant PE to maintain arterial blood pressure. Post-mortem histological evaluation of myocardial tissue samples was performed in separate groups of swine subjected to 2-weeks of RPO (n=8) and normal controls (n=5) to assess arteriolar density (α-smooth muscle actin staining) and structural remodeling (wall thickness/lumen diameter ratio). Results Submaximal ADO produced a significant ~60% rise in myocardial BF in normal controls, but this response was completely attenuated in the RPO group (Figure; A). The impaired vasodilator response to submaximal ADO in the RPO group was not explained by hemodynamic factors, as heart rate (RPO vs. control: 102±5 vs. 95±4 beats/min; p=0.29) and mean arterial pressure (71±3 vs. 67±5 mmHg; p=0.55) were similar between groups. However, group differences in ADO-induced vasodilation were abolished by administration of maximal ADO, which elicited a comparable ~4-fold rise in myocardial BF in normal controls and the RPO group. Arteriolar density (Figure; B) and arteriolar wall thickness/lumen diameter (Figure; C) were not different between groups, further supporting abnormal microvascular function as the primary mechanism underlying the impaired response to submaximal ADO after RPO. Conclusions These results indicate that RPO-induced HFpEF is characterized by an impairment in ADO-mediated coronary vasodilation that may compromise myocardial perfusion during episodes of increased metabolic demand. The absence of histopathological evidence of arteriolar structural remodeling along with a preserved vasodilator response to maximal ADO indicate that a functional abnormality is primarily responsible for the impaired responsiveness to ADO in this setting. Further studies are necessary to evaluate the contribution of endothelium-dependent vs. endothelium-independent factors, as well as whether therapeutic interventions targeting RPO-induced coronary microvascular dysfunction may prevent or reverse adverse myocardial remodeling and diastolic dysfunction in HFpEF.

Dynamic right and left ventricular interactions in the pig.

What is the central question of this study? Are the mechanisms that cause ventricular interdependence different when due to primary right to left ventricular pressure loading? What is the main finding and its importance? An instantaneous selective increase in aortic pressure causes an immediate increase in right ventricular end-systolic pressure independent of the pericardium, whereas a selective increase in pulmonary artery pressure decreases left ventricular diastolic compliance owing to a subsequent increasing right ventricular end-diastolic volume as a function of an intact pericardium limiting biventricular volume. Changes in contraction synchrony of either ventricle do not appear to be causing these effects. I characterized the dynamic factors determining ventricular interdependence with and without the pericardium. I measured right (RV) and left ventricular (LV) pressures and volumes simultaneously using conductance catheters in seven pentobarbitone-anaesthetized open-chested 5- to 7-week-old piglets. I studied these effects during apnoea, inferior vena caval occlusion and rapid partial aortic and pulmonary arterial occlusions. Conductance catheter-defined long-axis regional volumes were assessed to define regional contractile synchrony. Closed-pericardium measures were made from an initial (baseline) volume, then after two 20mlkg-1 fluid loads followed by an open-pericardium step. Baseline RV and LV volumes were similar. Aortic occlusion increased LV pressures and volumes and RV end-systolic pressure such that RV end-systolic elastance increased without changes in RV contraction synchrony, not affected by the pericardium. Pulmonary artery occlusion increased RV end-systolic pressure but not end-systolic volume. On the subsequent beat, RV end-diastolic pressure increased, whereas LV end-diastolic volume and diastolic compliance decreased. These effects were attenuated by opening the pericardium. Contraction synchrony across longitudinal segments was unaltered by either aortic or pulmonary artery occlusion. I conclude that the determinants of systolic and diastolic ventricular interdependence are different. Increasing RV pressures causes diastolic RV-to-LV interdependence, decreasing LV diastolic compliance and dependent on an intact pericardium. An increase in LV end-systolic pressure increases RV end-systolic elastance independent of the pericardium and has a minimal effect on RV diastolic function or contraction synchrony.

Adaptive Reductions in Left Ventricular Diastolic Compliance Protect the Heart From Stretch-Induced Stunning

Swine subjected to 2weeks of repetitive pressure overload (RPO) exhibited significant myocyte loss, but leftventricular (LV) systolic function was preserved, and chamber dilatation did not occur. Instead, myocardialremodeling characterized by myocyte hypertrophy and interstitial fibrosis led to a marked reduction in LV diastolic compliance, which protected the heart from stretch-induced myocyte injury and preserved LVejection fraction without anatomic LV hypertrophy. These results support a novel paradigm that links cardiacadaptations to RPO with the pathogenesis of reduced LV diastolic compliance and may explain howLVstiffening can occur in the absence of sustained hypertension or anatomic hypertrophy.

The overloaded right heart and ventricular interdependence.

The right and the left ventricle are interdependent as both structures are nested within the pericardium, have the septum in common and are encircled with common myocardial fibres. Therefore, right ventricular volume or pressure overloading affects left ventricular function, and this in turn may affect the right ventricle. In normal subjects at rest, right ventricular function has negligible interaction with left ventricular function. However, the right ventricle contributes significantly to the normal cardiac output response to exercise. In patients with right ventricular volume overload without pulmonary hypertension, left ventricular diastolic compliance is decreased and ejection fraction depressed but without intrinsic alteration in contractility. In patients with right ventricular pressure overload, left ventricular compliance is decreased with initial preservation of left ventricular ejection fraction, but with eventual left ventricular atrophic remodelling and altered systolic function. Breathing affects ventricular interdependence, in healthy subjects during exercise and in patients with lung diseases and altered respiratory system mechanics. Inspiration increases right ventricular volumes and decreases left ventricular volumes. Expiration decreases both right and left ventricular volumes. The presence of an intact pericardium enhances ventricular diastolic interdependence but has negligible effect on ventricular systolic interdependence. On the other hand, systolic interdependence is enhanced by a stiff right ventricular free wall, and decreased by a stiff septum. Recent imaging studies have shown that both diastolic and systolic ventricular interactions are negatively affected by right ventricular regional inhomogeneity and prolongation of contraction, which occur along with an increase in pulmonary artery pressure. The clinical relevance of these observations is being explored.

The Effect of Trabeculae Carneae on Left Ventricular Diastolic Compliance: Improvement in Compliance With Trabecular Cutting.

The role of trabeculae carneae in modulating left ventricular (LV) diastolic compliance remains unclear. The objective of this study was to determine the contribution of trabeculae carneae to the LV diastolic compliance. LV pressure-volume compliance curves were measured in six human heart explants from patients with LV hypertrophy at baseline and following trabecular cutting. The effect of trabecular cutting was also analyzed with finite-element model (FEM) simulations. Our results demonstrated that LV compliance improved after trabecular cutting (p < 0.001). Finite-element simulations further demonstrated that stiffer trabeculae reduce LV compliance further, and that the presence of trabeculae reduced the wall stress in the apex. In conclusion, we demonstrate that integrity of the LV and trabeculae is important to maintain LV stiffness and loss in trabeculae leads to more LV compliance.

The right ventricle: interaction with the pulmonary circulation.

The primary role of the right ventricle (RV) is to deliver all the blood it receives per beat into the pulmonary circulation without causing right atrial pressure to rise. To the extent that it also does not impede left ventricular (LV) filling, cardiac output responsiveness to increased metabolic demand is optimized. Since cardiac output is a function of metabolic demand of the body, during stress and exercise states the flow to the RV can vary widely. Also, instantaneous venous return varies widely for a constant cardiac output as ventilatory efforts alter the dynamic pressure gradient for venous return. Normally, blood flow varies with minimal changes in pulmonary arterial pressure. Similarly, RV filling normally occurs with minimal increases in right atrial pressure. When pulmonary vascular reserve is compromised RV ejection may also be compromised, increasing right atrial pressure and limiting maximal cardiac output. Acute increases in RV outflow resistance, as may occur with acute pulmonary embolism, will cause acute RV dilation and, by ventricular interdependence, markedly decreased LV diastolic compliance, rapidly spiraling to acute cardiogenic shock and death. Treatments include reversing the causes of pulmonary hypertension and sustaining mean arterial pressure higher than pulmonary artery pressure to maximal RV coronary blood flow. Chronic pulmonary hypertension induces progressive RV hypertrophy to match RV contractility to the increased pulmonary arterial elastance. Once fully developed, RV hypertrophy is associated with a sustained increase in right atrial pressure, impaired LV filling, and decreased exercise tolerance. Treatment focuses on pharmacologic therapies to selectively reduce pulmonary vasomotor tone and diuretics to minimize excessive RV dilation. Owning to the irreversible nature of most forms of pulmonary hypertension, when the pulmonary arterial elastance greatly exceeds the adaptive increase in RV systolic elastance, due to RV dilation, progressive pulmonary vascular obliteration, or both, end stage cor pulmonale ensues. If associated with cardiogenic shock, it can effectively be treated only by artificial ventricular support or lung transplantation. Knowing how the RV adapts to these stresses, its sign posts, and treatment options will greatly improve the bedside clinician’s ability to diagnose and treat RV dysfunction.

Peripheral Venous Pressure as an Indicator of Preload Responsiveness During Volume Resuscitation from Hemorrhage.

Fluid resuscitation of hypovolemia presumes that peripheral venous pressure (PVP) increases more than right atrial pressure (RAP), so the net pressure gradient for venous return (PVP-RAP) rises. However, the heart and peripheral venous system function under different compliances that could affect their respective pressures during fluid infusion. In a porcine model of hemorrhage resuscitation, we examined whether RAP increases more than PVP, thereby reducing the venous return pressure gradient and blood flow. Anesthetized pigs (n = 8) were bled to a mean arterial blood pressure of 40 mm Hg and resuscitated with stored blood and albumin for pulmonary artery occlusion pressures (PAOPs) of 5, 10, 15, and 20 mm Hg. Venous pressures, inferior vena cava blood flow (ultrasonic flowprobe), and left ventricular diastolic compliance (Doppler echocardiography) were measured. Stroke volume variability was calculated. With volume resuscitation, the slope of RAP exceeded PVP (P ≤ 0.0001) when PAOP is 10 to 20 mm Hg, causing the pressure gradient for venous return to progressively decrease. Inferior vena cava blood flow did not further increase after PAOP > 10 mm Hg. The E/e' ratio increased (P = 0.001) during resuscitation indicating reduced diastolic compliance. A significant curvilinear relationship was found between PVP and stroke volume variability (R = 0.62; P < 0.001), where fluid responders had PVP < 15 mm Hg. Fluid resuscitation above a PAOP 10 mm Hg reduces myocardial compliance and reduces the venous return pressure gradient. The hemodynamic response to fluid resuscitation becomes limited by diastolic properties of the heart. PVP measurement during hemorrhage resuscitation may predict fluid responsiveness and nonresponsiveness.

N-terminal-pro-brain natriuretic peptide elevations in the course of septic and non-septic shock reflect systolic left ventricular dysfunction assessed by transpulmonary thermodilution

BackgroundThe cardiac correlates, if any, of N-terminal probrain natriuretic peptide (NT-proBNP) levels in septic and non-septic shock patients remain controversial. MethodsIn the 38 septic and 22 non-septic shock patients in the transpulmonary thermodilution arm of a previous 2-center randomized controlled trial comparing pulmonary artery catheterization with transpulmonary thermodilution, serial (daily for 3days) and paired measurements (n=145) were obtained of NT-proBNP and transpulmonary dilution variables as global ejection fraction (GEF), left ventricular preload-recruitable stroke work (PRSW) and diastolic compliance. ResultsElevated NT-proBNP inversely related to low GEF and PRSW in pooled data (r=−0.45, P<0.001). The 72h course of NT-proBNP was inversely associated with PRSW, independent of age, gender, creatinine, norepinephrine treatment and diastolic compliance, without differences between septic and non-septic shock. Over the 72h study period, NT-proBNP levels were higher in 28day non-survivors than survivors, independent of type of shock and disease severity. ConclusionsIn septic and non-septic shock, NT-proBNP elevations reflect systolic left ventricular dysfunction and are associated with a poor outcome. They may help recognition of cardiac dysfunction in shock and its management when invasive hemodynamic monitoring is not yet instituted.

Abstract 11639: Interpretation of Diastolic Function in Hemodialysis Patients: The Importance of a Load Independent Index of Left Ventricular Diastolic Compliance

Background: Prior studies of diastolic function in the setting of end-stage renal disease (ESRD) primarily utilize E/e’, a volume dependent measure of left ventricular (LV) filling pressure. While such studies show that high E/e’ is common and associated with adverse outcomes in ESRD, these findings may not be attributable to intrinsic diastolic function. In contrast to E/e’, the LV end-diastolic pressure-volume relationship (EDPVR) (a load independent index of LV diastolic compliance) describes intrinsic LV diastolic function. Therefore, we sought to examine the effects of hemodialysis on EDPVR, and to delineate correlates of EDPVR in the setting of ESRD. We hypothesized that E/e’ and other indices of diastolic function are volume dependent in ESRD, while EDPVR is not. Methods: Twenty-nine patients underwent echocardiography directly before and during the last hour of dialysis. LV diastolic compliance was quantified using a single-beat EDPVR method (P = αVβ). The LV end-diastolic volume at an idealized pressure of 20 mmHg (EDV20) was calculated as a means of comparing EDPVR curves within and between patients (smaller EDV20 = lower diastolic compliance). Results: During hemodialysis, EDV20 did not significantly change (median [IQR] pre-dialysis EDV20 112 [93-113] ml; intra-dialysis EDV20 113 [94-138] ml; p=0.2). However, E/e’ decreased on average by 1.2 absolute units (AU) (median [IQR] pre-dialysis 7.0 [6.0-8.9] AU; intra-dialysis 6.0 [5.1-9.7] AU; p=0.004). E/e’ decreased by 2 AU for every 1 L/hr ultrafiltration rate (p=0.07). Significant correlates of lower pre-dialysis EDV20 (stiffer LV) included higher diastolic blood pressure (DBP) (β=-13 ml EDV20 per 10 mmHg DBP, p=0.005) and concentric LV remodeling, (β=-5ml EDV20 per 0.1 g/ml LV mass/volume ratio, p=0.004). NT-proBNP was associated with higher E/e’, (β=0.2 E/e’ per 1000 pg/ml higher NT-proBNP, p&lt;0.001), but was not a significant correlate of EDV20 (p=0.5). Conclusions: LV end-diastolic compliance (EDV20) is less volume dependent than LV filling pressures (E/e’) in the setting of ESRD, and thus may be a better measure of intrinsic diastolic function than E/e’. Further studies are needed to determine whether EDV20 predicts adverse outcomes in the ESRD population.

Variations of left ventricular-arterial coupling in septic shock

To explore the variations of left ventricular-arterial coupling and elucidate its mechanisms in septic shock. Septic shock rabbits were established by an intravenous injection of endotoxin. A total of 12 rabbits were divided randomly into sham operation group (S, n = 6) and endotoxin injection group (E, n = 6). Ultrasonic echocardiography and hemodynamic monitoring were conducted at 0h (30-min post-operation), 2h (1-hour after endotoxin or saline injection) and 4h (3-hour after endotoxin or saline injection) and the relative hemodynamic indices were recorded. (1) In E group, end-systolic elastance (Ees) at 2h was lower than that at 0h (75.72 ± 5.16 vs 90.77 ± 7.17 mm Hg/ml) and Ees at 4h was lower than that at 2h (58.45 ± 3.63 vs 75.72 ± 5.16 mm Hg/ml, P < 0.05); (2) In E group, left ventricular diastolic volume (LVDV) at 2h and 4h were both lower than that at 0h (3.26 ± 0.21 vs 3.58 ± 0.25 ml, 3.27 ± 0.19 vs 3.58 ± 0.25 ml). And left ventricular end diastolic compliance (Ced) at 4h were lower than that at 0h and 2h (0.61 ± 0.05 vs 0.74 ± 0.07 ml/mm Hg, 0.61 ± 0.05 vs 0.75 ± 0.08 ml/mm Hg, P < 0.05); (3) In E group, Ea at 2h and 4h was lower than that at 0h (41.35 ± 2.87 vs 50.46 ± 3.22 mm Hg/ml, 40.13 ± 2.68 vs 50.46 ± 3.22 mm Hg/ml, P < 0.05); (4) In E group, Ea/Ees at 4h was higher than that at 0h and 4h (0.70 ± 0.07 vs 0.57 ± 0.06, 0.70 ± 0.07 vs 0.56 ± 0.05, P < 0.05). And Ea/Ees at 2h had no significant difference with that at 0h (0.56 ± 0.05 vs 0.57 ± 0.06, P < 0.05). During compensatory stage of septic shock, left ventricular-arterial coupling shows no significant variation. However, during decompensatory stage of septic shock, there is significant left ventricular-arterial decoupling. The main reason for decoupling lies in that the decrease of left myocardial contractility is more significant than that of left ventricular afterload. And ventricular diastolic dysfunction may also participate.

Left Ventricular Dysfunction Induced by Nonsevere Idiopathic Pulmonary Arterial Hypertension

Severe increase in right ventricular pressure can compromise left ventricular (LV) function because of impaired interventricular interaction and aggravate the symptoms. To elucidate how nonsevere idiopathic pulmonary arterial hypertension (IPAH) influences LV function because of impaired interventricular interaction. Invasive pressure-volume (PV) loop analysis obtained by conductance catheterization was performed at rest and during atrial pacing in patients with mild IPAH (n = 10) compared with patients with isolated LV diastolic dysfunction (DD) (n = 10) and control subjects without heart failure symptoms (n = 9). Patients with nonsevere IPAH (pulmonary artery pressure mean 29 ± 5 mm Hg) and patients with DD showed preserved systolic (ejection fraction 63 ± 12% and 62 ± 9%) and impaired LV diastolic function at rest (LV stiffness 0.027 ± 0.012 ml(-1) and 0.029 ± 0.014 ml(-1)). During pacing at 120 per minute patients with IPAH and DD decreased their stroke volume (-25% and -30%; P < 0.05) and failed to increase cardiac output significantly. Opposite to patients with DD and control subjects, temporary preload reduction during inferior vena cava occlusion initially induced an expansion of LV end-diastolic volume in IPAH (+7%; P < 0.05), whereas end-diastolic pressure continuously dropped. This resulted in an initial downward shift to the right of the PV loop indicating better LV filling, which was associated with a temporary improvement of cardiac output (+11%; P < 0.05) in the patients with IPAH, but not in patients with DD and control subjects. Mild idiopathic pulmonary arterial pressure impairs LV diastolic compliance even in the absence of the intrinsic LV disease and contributes to the reduced cardiac performance at stress.

Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction

Patients with heart failure with preserved ejection fraction (HFpEF) have an increased mortality and morbidity similar to patients with systolic heart failure and reduced ejection fraction.1 The incidence of HFpEF is increasing,2 and roughly 30% to 50% of all patients with heart failure have a normal ejection fraction.3 The underlying pathophysiology is increased left ventricular diastolic stiffness that leads to high filling pressures.4,5 Additionally, left ventricular hypertrophy,6 accumulation of cardiac collagen,7 endothelial dysfunction,8 a shift in titin isoform, and increased passive stiffness of cardiac myocytes9 all contribute to these changes. For reasons that are yet uncertain, a subset of patients with HFpEF will go on to develop pulmonary hypertension (PH). Patients with HFpEF and PH can be subdivided into those with a normal pulmonary vascular resistance (PVR) and those with an increased PVR and pulmonary arterial remodeling. In fact, patients with HFpEF account for a significant percentage of patients with PH and right-sided heart dysfunction.10 Article see p 164 Importantly, both PH and right ventricular dysfunction are associated with decreased survival compared with HFpEF patients without PH.11 Although the underlying pathophysiology is poor left ventricular diastolic compliance, treatment focused on improving stiffness has been lacking, and management of patients with HFpEF has focused on control of factors known to exert effects on left ventricular end-diastolic pressure. The main emphasis has been on aggressive treatment of systemic blood pressure and heart rate, limiting pressure and volume overload of …