LV Diastolic Stiffness Research Articles

Abstract Mo113: An Ovary-Intact Postmenopausal HFpEF Animal Model.

Background: The incidence of HFpEF in women significantly escalates following the age of menopause. This trend cannot solely be attributed to chronological aging, as evidenced by the more gradual increase in prevalence among men with HFpEF. This pattern suggests that menopause is a provocative event for HFpEF. However, the underlying mechanisms remain elusive and challenging to investigate in human subjects; moreover, the attempt to create HFpEF in ovariectomized (OVX) mice was unsuccessful. We aim to create an animal model of postmenopausal HFpEF that resembles the characteristics of HFpEF in women with natural menopause. Methods: We use the 4-vinyl cyclohexene dioxide (VCD) to induce “ovary-intact” menopause, combined with the 2hit regimen (HFpEF inducing regimen elicited by high-fat diet and nitric oxide synthase inhibitor) to model postmenopausal HFpEF. VCD gradually causes ovarian failure, providing the perimenopausal transition and preserving residual ovarian stroma, mimicking natural menopause. The HFpEF phenotypes were studied at the in vivo LV by pressure-volume (PV) analysis and at the single cell level by intact cell force measurement. Results: The Female-VCD-2hit model demonstrates diastolic dysfunction at both the LV and the cellular levels. At the LV level, the increase in the end-diastolic pressure-volume relation (EDPVR) stiffness coefficient and LV end-diastolic pressure (LVEDP) indicates a heightened stiffness of the LV chamber and an elevation in LV filling pressure, an HFpEF-like condition. At the cardiomyocyte level, the female-VCD-2hit model exhibits an increase in cellular diastolic stiffness, suggesting that the observed LV diastolic stiffness is derived from the stiffness of the cardiomyocytes. We compared the female-VCD-2hit mice with the OVX mice subjected to the 2hit regimen. The 2hit-OVX model showed a milder form of diastolic dysfunction, observed as a smaller increase in LV diastolic stiffness (EDPVR) and normal LV filling pressure (LVEDP). Conclusions: Female mice, either premenopausal or ovariectomized, are more resistant to the development of HFpEF, unlike their ovary-intact menopausal (VCD-treated) counterparts, which exhibit a vulnerability to HFpEF, making the VCD-2hit model a suitable model to study postmenopausal HFpEF. The LV diastolic dysfunction observed in the 2hit model is attributed to mechanical dysfunction at the cardiomyocyte level.

Lower muscular strength is associated with smaller left and right chambers and lower cardiac mass in the general population – The Sedentary's Heart

BackgroundThe cardiac muscle has the ability to adapt to different loading conditions. We analyzed the associations of the age-related decreasing handgrip strength (HGS), a marker of muscular fitness, on cardiac structure and function in a community-based sample. MethodsWe performed cross-sectional analyses of 4646 subjects (2554 women; 55.0%) aged 20 to 93 years from two independent cohorts of the Study of Health in Pomerania (SHIP-2 and SHIP-TREND-0). We analyzed the associations of HGS with structural and functional left and right ventricular (LV and RV) and left atrial (LA) parameters as determined by echocardiography and magnetic resonance imaging (MRI) as well with log-transformed NT-proBNP values using multivariable-adjusted linear regression models. ResultsMRI data showed that a 1 kg lower HGS was associated with a 0.40 mL (95% confidence interval: 0.26 to 0.54; p < 0.001) lower LV end-diastolic volume, a 0.011 mm (0.005 to 0.018; p = 0.001) lower LV wall-thickness, a 0.59 g (0.43 to 0.75; p < 0.001) lower LV mass, a 0.58 mL/beat (0.43 to 0.74; p < 0.001) lower LV stroke volume, a 0.03 L/min (0.02 to 0.04; p < 0.001) lower LV cardiac output, a 0.48 mL (0.27 to 0.68; p < 0.001) lower LA end-diastolic volume, and a 1.02 mL (0.71 to 1.32) lower RV end-diastolic volume. Similar findings were observed for echocardiographic parameters. Moreover, lower HGS was associated with higher echocardiographic LV diastolic stiffness and NT-proBNP levels. ConclusionsIn this large population-based sample, lower muscular fitness as assessed by HGS was associated with lower LV wall thickness and mass as well as with smaller chamber size, stroke volume and cardiac output of the LV, LA and RV. Moreover, HGS was inversely related to LV diastolic stiffness and NT-proBNP values. These outcomes might demonstrate the effects of an aging-related decrease in physical activity and lower muscular fitness on the heart - “the sedentary's heart”.

Abstract 336: The Effect Of Phosphodiesterase 9a Inhibition In 2 Mouse Models Of Diastolic Dysfunction

Low myocardial cGMP-PKG activity is associated with increased cardiomyocyte stiffness in HFpEF. cGMP is mainly hydrolyzed by PDE (phosphodiesterases)5a and PDE9a. Importantly, PDE9a protein expression was reported to be upregulated in human HFpEF myocardium and chronic administration of PDE9a inhibitor reversed pre-established cardiac hypertrophy and systolic dysfunction in mice subjected to TAC (Transverse Aortic Constriction). We evaluated whether PDE9a inhibition had a beneficial effect on diastolic dysfunction (DD). We investigated two mouse models of DD: 1) TAC-DOCA (TAC with deoxycorticosterone acetate (DOCA) supplementation) and 2) LepR db/db , a metabolically induced DD models. Mice were subjected to subcutaneous implantation with osmotic minipumps containing either PD9a inhibitor (PF-4449613) or vehicle for 4 wks. PDE9a transcript was not upregulated in myocardium of either TAC-DOCA or LepR db/db mice. PV analysis revealed that in TAC-DOCA mice, inhibition of PDE9a resulted in reduced LV diastolic stiffness, but impairment of systolic function observed as ventricular-vascular decoupling. In LepR db/db mice, cardiomyocyte stiffness was slightly but significantly reduced in PDE9a inhibitor treated animals. No differences in myocardial fibrosis or cardiac morphometry were observed. The effect of acute PDE9a inhibition was investigated in intact cardiomyocytes isolated from LVs of TAC-DOCA mice. Cellular work loop force measurement was conducted before and after administration of PDE9a inhibitor combined with ANP (Atrial Natriuretic Peptide) for 15 mins. Cardiomyocytes from TAC-DOCA had high diastolic stiffness compared to sham hearts, however, no stiffness reduction was observed after acute inhibitor treatment. Conclusion: Chronic inhibition of PDE9a ameliorates LV diastolic stiffness, but suppresses systolic function in TAC-DOCA induced DD mice. The LV stiffness reduction is in part due to cardiomyocyte stiffness reduction. The advantage of PDE9a inhibition on diastolic function might be more evident, with less systolic suppression, in hearts with PDE9a upregulation.

AnatoMy and physIopathoLogy of the heArt in a ceNtenarian cOhort (MILANO study)

Centenarians are increasingly being encountered in clinical practice. The aim of the study was to characterize centenarians' clinical features and cardiovascular system. A prospective, observational, cross-sectional, case-control study included 118 hospitalized >100-year-old patients compared to 50 octogenarians, selected in Milan (Italy) from December 2010 to December 2017, to assess their clinical and echocardiographic characteristics. Centenarians were mostly women with small body surface area; long history of hypertension; chronic renal failure; and low incidence of smoking, diabetes, dyslipidemia, hyperuricemia, coronary artery disease, atrial fibrillation, and cerebrovascular disease. They showed high prevalence of severe cognitive impairment and disability. Almost half of patients (46%) were hospitalized for congestive heart failure (HF), mostly diastolic (80% of cases). Centenarians' hearts had reduced left ventricular end-diastolic dimensions (25.3 ± 3.8 mm/m^2), increased septal thickness (13.3 ± 1.9 mm), and higher relative wall thickness (0.58 ± 0.1). The ejection fraction was usually normal and rarely depressed (57.1% ± 11.7%), whereas the E/e’ ratio was considerably increased (17.0 ± 6.0). Noninvasive evaluation of ventricular-arterial coupling parameters revealed significantly higher values of LV end-diastolic elastance in all centenarians versus octogenarians (0.4 ± 01 mm Hg/mL/m^2 vs 0.18 ± 0.2 mm Hg/mL/m^2, P < .0001) and in centenarians with HF versus those without HF (0.5 ± 0.1 mm Hg/mL/m^2 vs 0.34 ± 0.1 mm Hg/mL/m^2, P < .0001). The centenarians' cardiovascular system manifested a significant increase in LV diastolic stiffness with consequent susceptibility to diastolic HF. A progressive afterload increase and a passive load independent mechanism could have contributed to such changes.

Cardiac Specific Gene Delivery of the Natriuretic Peptide Receptor Improves Diastolic Function in a Canine Model of HFpEF.

Introduction Natriuretic peptides stimulate guanylyl cyclase-A (GCA) to produce cGMP. Deficient myocardial cGMP signaling has been implicated in the pathogenesis of diastolic dysfunction and heart failure (HF) with preserved ejection fraction (HFpEF). We hypothesized that cardiac specific over-expression of GCA via gene-delivery with an adeno-associated virus-9 (AAV9-GCA) vector will enhance response to endogenous natriuretic peptides and improve diastolic dysfunction in experimental HFpEF. Methods The HFpEF model included unilateral renal wrapping (RW) to induce hypertension plus DOCA-salt exposure in aged beagles. Trans-catheter (C-cath®) endocardial injections (≈ 14 per dog) of AAV9-GCA or placebo were performed 2 weeks prior to RW. HFpEF+Placebo (n=8) and HFpEF+AAV9-GCA (n=8) underwent echo and invasive pressure-volume analysis at 11 weeks post-RW. Aged Control (n=6) dogs (no RW) were also studied. In HFpEF dogs, systemic blood pressure (BP) was monitored weekly with an implanted CardioMEMS sensor. All dogs underwent a bio-assay to exclude anti-AAV9 antibodies prior to treatment. Results At end study, as compared to Control dogs, HFpEF+Placebo dogs had higher EF (67% vs 63%, p=0.03), relative wall thickness (RWT; 0.55 vs 0.47, p Conclusion Catheter based, cardiac specific gene delivery of GCA in experimental HFpEF was feasible, resulted in persistent GCA over-expression at 13 weeks post-delivery and was associated with improved LV diastolic stiffness.

Lower diastolic wall strain is associated with coronary revascularization in patients with stable angina

BackgroundLeft ventricular (LV) diastolic dysfunction occurs earlier in the ischemic cascade than LV systolic dysfunction and electrocardiographic changes. Diastolic wall strain (DWS) has been proposed as a marker of LV diastolic stiffness. Therefore, the objectives of this study were to define the relationship between DWS and coronary revascularization and to evaluate other echocardiographic parameters in patients with stable angina who were undergoing coronary angiography (CAG).MethodsFour hundred forty patients [mean age: 61 ± 10; 249 (57%) men] undergoing CAG and with normal left ventricular systolic function without regional wall motion abnormalities were enrolled. Among them, 128 (29%) patients underwent revascularization (percutaneous intervention: 117, bypass surgery: 11). All patients underwent echocardiography before CAG and the DWS was defined using posterior wall thickness (PWT) measurements from standard echocardiographic images [DWS = PWT(systole)-PWT(diastole)/PWT(systole)].ResultsPatients who underwent revascularization had a significantly lower DWS than those who did not (0.26 ± 0.08 vs. 0.38 ± 0.09, p < 0.001). Age was comparable between the two groups (61 ± 9 vs. 60 ± 11, p = 0.337), but the proportion of males was significantly higher among patients who underwent revascularization (69 vs. 52%, p = 0.001). The LV ejection fraction was similar but slightly decreased (60.9 ± 5.7 vs. 62.4 ± 6.2%, p = 0.019) and the E/E’ ratio was elevated (10.3 ± 4.0 vs. 9.0 ± 3.1, p < 0.001) among patients who underwent revascularization. In multiple regression analysis, lower DWS was an independent predictor of revascularization (cut-off value: 0.34; sensitivity: 89%; AUC: 0.870; SE: 0.025; p < 0.001).ConclusionDWS, a simple parameter that can be calculated from routine 2D echocardiography, is inversely associated with the presence of coronary artery disease and the need for revascularization.

Ventricular-vascular dynamics in pediatric patients with heart failure and preserved ejection fraction

ObjectiveThe details of the ventricular-vascular dynamics of heart failure with preserved ejection fraction (HFpEF) in children remain poorly understood. We tested the hypothesis that pediatric HFpEF patients have ventricular systolic, diastolic, and arterial stiffening at rest as well as impaired reserve function associated with coronary supply/demand imbalance. MethodsWe studied the ventricular pressure-area relationship in 22 pediatric HFpEF patients and 22 control subjects before and after dobutamine infusion and during abdominal compression. Coronary supply/demand balance was assessed by subendocardial viability ratio (SEVR) calculated from the aortic pressure waveform. ResultsCompared with controls, the HFpEF patients had significantly higher end-systolic (Ees) and arterial (Ea) elastance. Increased ventricular diastolic stiffness also occurred in the HFpEF patients, resulting in modest elevation of end-diastolic pressure (EDP) at rest (13.6±4.3 vs. 7.3±2.3mmHg, P<0.0001). The difference in EDP became more evident with a preload increase through abdominal compression, indicating a limited diastolic reserve in HFpEF patients (EDP changes; 11.3±6.2 for HFpEF vs. 3.4±0.6mmHg for controls, P=0.016). The HFpEF patients exhibited impaired beta-adrenergic reserve in ventricular contractility and ventricular-arterial coupling in response to dobutamine infusion. SEVR was significantly lower in the HFpEF (0.64±0.11) than in the control (0.79±0.07, P<0.0001) and was significantly correlated with LV diastolic stiffness and dobutamine-induced changes in ventricular contractility. ConclusionsHFpEF in children involves higher ventricular-arterial stiffness at rest as well as impaired systolic and diastolic reserve, which closely correlate with impaired coronary supply/demand balance.

Abstract 12002: Increasing Heart Rate in Left Bundle Branch Block Results in Incomplete Relaxation and Increases Left Ventricular Diastolic Stiffness

Introduction: Left bundle branch block (LBBB) slows LV pressure decay and shortens diastole. At low heart rates (HR) this may not compromise filling as diastolic duration is sufficient for complete relaxation. Purpose: We investigated if further abbreviation of diastole at increased HR could cause incomplete relaxation, particularly in the late activated LV lateral wall; thereby increasing diastolic LV stiffness, which may cause increased filling pressure. Methods: We analyzed data from a study of 10 canines where HR was increased from 120 to 140 by atrial pacing before and after induction of LBBB. Ventricular and pericardial pressures, LV volume and regional segment lengths (SL) were measured. Global diastolic stiffness was calculated from end diastolic (ED) transmural LV pressure-volume (PV) relations and regional stiffness from pressure-SL relations in septum and lateral wall. A mathematical model was used to estimate the increase in filling pressure due to incomplete relaxation at HR 160 and 180. Results: In LBBB, tau was prolonged and diastole abbreviated at both HR 120 and 140, compared to baseline (Fig. 1). Increased HR during LBBB stiffened the ventricle, seen as an upward shift of the ED PV relation by 1.4±1.7 mmHg (±SD), (p=0.03) whereas no shift (-0.9±1.5 mmHg) (NS) was seen at baseline (Fig. 2). Regional ED P-SL relations showed a larger upward shift of the lateral wall (1.1±1.8 mmHg) and hence a more pronounced stiffening compared to the septum (0.6±1.5 mmHg) (p&lt;0.05), indicating more delayed lateral wall relaxation. Mathematical estimation showed an increase in filling pressure of 7 and 16 mmHg due to further diastolic abbreviation at HR 160 and 180, respectively. Conclusions: LV diastolic stiffness is increased at high heart rates in LBBB due to incomplete relaxation, particularly of the late activated LV lateral wall. Diastolic stiffening by increased HR may lead to exercise intolerance and dyspnoea in LBBB patients due to elevated filling pressure.

Abstract 16054: Ventricular-Arterial Coupling Biphasically Correlates to Ventricular Diastolic Chamber Stiffness in Children–Association With Aldosterone Activation

Introduction: Left ventricular–arterial coupling (LVAC), the ratio of end–systolic to effective arterial elastance (Ees/Ea), determines end–systolic pressure and stroke volume in a given preload. LV diastolic chamber stiffness (LV–K) is an important diastolic property to affect LV filling. However, the relationship between Ees/Ea and LV–K in children remains unestablished. Aldosterone (ALD) accelerates LV and arterial stiffening. Hypothesis: This study was undertaken to test the hypothesis that Ees/Ea may affect LV–K through ALD regulation in children. Methods: During catheterizations for children with biventricular circulation (N=75, median 2.5 years), blood samples for ALD were collected, and LV pressure and area relationships (PAR) were recorded using high-fidelity pressure–guidewire and echocardiographic AQ method during steady state and transient IVC occlusion. LV–K was obtained by dividing the pressure difference between LV minimal and end-diastolic pressure (EDP) by stroke volume. ALD levels were transformed into common logarithm. Results: Ees/Ea biphasically correlated to LV–K, which was approximated by downward convex parabola with a minimum at 0.9 of Ees/Ea (R=0.61, P&lt;0.0001). Ees/Ea also bipahsically correlated to log ALD, which was approximated by downward convex parabola with a minimum at 0.8 of Ees/Ea (R=0.45, P&lt;0.005). Moreover, LV–K linearly correlated to log ALD (R=0.38, P&lt;0.005). There was no significant relationship between LV–K and relative wall thickness. Conclusions: To our knowledge, this is the first study to demonstrate that Ees/Ea bipahsically correlated to LV–K and ALD. Dilated LV with low Ees/Ea accompanies elevated filling pressure and shows restrictive physiology with higher LV–K. On the other hand, when Ees/Ea is higher than normal range, this study indicates that there should be an increased LV diastolic stiffness which is not always associated with wall hypertrophy. Because LVAC abnormality may induce LV stiffening associated with ALD activation, chronic inhibition therapy of renin–angiotensin system to keep Ees/Ea within appropriate range may inhibit LV stiffening directly and through LVAC &amp; LV–K interaction.

Abstract 11808: Association Between Left Ventricular Properties in Patients With Hypertension and the Incidence of Paroxysmal Atrial Fibrillation: Three-Dimensional Speckle Tracking Echocardiographic Study

Background: Hypertension (HTN) is one of the major causes of atrial fibrillation (AF), since it is usually accompanied by left atrial (LA) remodeling due to pressure and/or volume (LAV) overload. We examined the relationship between ventricular (LV) geometry or LV properties in HTN and the incidence of paroxysmal AF (PAF) using novel, one-beat, automated, 3-dimensional speckle tacking echocardiography (3D-STE) with high volume rates. Methods: Patients with HTN (n=107, age 69±7) and controls (n=60, age 69±9) were prospectively enrolled. HTN patients were divided into 5 groups according to LV geometry and the presence of hypertensive heat failure (HHF) {normal geometry (n=25), concentric remodeling (n=20), concentric hypertrophy (LVH) (n=24), eccentric LVH (n=21) and HHF (n=17)}. Isovolumic relaxation time (IVRT) was measured by Doppler echo. We evaluated LV ejection fraction (EF), E/e’, pulmonary capillary wedge pressure (PCWP), Tau, LV diastolic stress, LV strain and LV myocardial stiffness in sinus rhythm. PCWP was estimated as 10.7- 12.4 x log (LA active emptying function / minimum LAV) as we reported. Tau was calculated as IVRT / (ln 0.9 x systolic blood pressure - ln PCWP). LV diastolic stress was calculated as LV radius at end diastole x PCWP / thickness. LV strain rate (SR) during IVR, as an index of relaxation, and LV strain were measured by the 3D-STE with volume rates of 50-80vps. LV myocardial stiffness was estimated as LV stress / LV strain. Results: LVEF was reduced only in HHF compared with controls (56±7 vs. 67±6%). Conclusion: LVEF in HHF was decreased but still remained within the normal range, whereas diastolic properties in eccentric LVH and HHF were reduced compared with control. The incidence of PAF significantly increased in eccentric LVH and HHF associated with the impairment of LV relaxation and stiffness and increased LV stress. This suggests that the target of treatment to reduce the incidence of PAF in HTN must be diastolic function.

Impact of chronic changes in arterial compliance and resistance on left ventricular ageing in humans.

Left ventricular systolic elastance (Ees) and diastolic elastance (Eed) correlate with arterial elastance (Ea), but it is unknown how chronic changes in arterial compliance and resistance, which determine Ea, might differentially affect cardiac properties with ageing. We sought to characterize chronic changes in pulsatile and resistive arterial load and correlate them with longitudinal changes in LV structure and function in a prospective, community-based study. Comprehensive echocardiography was performed in 722 subjects participating in a randomly selected community-based study at two examinations separated by 4 years, allowing for assessment of LV Ees, Eed, and end-diastolic volume (EDV), Ea, total arterial compliance, and systemic vascular resistance at both examinations. Chronic changes in resistance and heart rate were the dominant contributors to change in Ea. Changes in arterial compliance had little impact on changes in Ea, but were strongly associated with changes in Ees. The combination of increased resistance and decreased compliance was associated with the largest increase in LV diastolic stiffness, an effect that was mediated by a decrease in LVEDV. In contrast, subjects with both improved arterial compliance and decreased resistance displayed an increase in LVEDV over time, with no increase in LV Eed. Increases in pulsatile arterial load with ageing contribute more to LV systolic stiffening, while combined pulsatile and resistive loading changes are associated with positive and negative chamber remodelling and diastolic stiffness. Therapies designed to improve arterial resistance and particularly to enhance aortic compliance may hold promise to prevent or reverse cardiac ageing and its sequelae.

Heart failure and galectin 3.

Innovations in medical diagnosis and treatment have led to prolongation of life of patients. Increasing the life expectancy of cardiac patients and thereby increasing the prevalence of heart failure (HF). Currently more than one million hospital admissions per year are due to HF and it has been estimated that the cost is approximately $39 billion annually in the U.S. There are two pathophysiologic myocardial mechanisms that cause HF: systolic dysfunction and diastolic dysfunction. Normal cardiac aging is characterized by morphological and structural changes that increase cardiomyocyte size, increased number of apoptosis with decreased number in myocytes, increased collagen deposition, and functional changes at cellular level. All these factors contribute to fibrotic remodeling that leads to LV diastolic stiffness, which ultimately leads to impaired diastolic function. At the same time it has been shown that galectin-3, a soluble β-galactoside-binding protein secreted by activated macrophages, promotes cardiac fibroblast proliferation, collagen deposition, and ventricular dysfunction. In this paper we review the prognostic value of galectin-3 as an independent predictor of mortality in patients with moderate to advanced chronic HF (CHF).

Impact of General and Central Adiposity on Ventricular-Arterial Aging in Women and Men

ObjectivesThe aim of this study was to assess the effects of central and general obesity measures on long-term longitudinal changes in ventricular-arterial mechanics. BackgroundObesity, female sex, and ventricular-arterial stiffening are associated with the development of heart failure with preserved ejection fraction. Fat distribution and chronic changes in body composition may affect longitudinal changes in LV properties, independent of arterial load. MethodsIn 1,402 subjects from a randomly selected, community-based population, comprehensive echo-Doppler echocardiography was performed at two examinations separated by 4 years. From this population, 788 subjects had paired data adequate for determining left ventricular end-systolic elastance (Ees), end-diastolic elastance (Eed), and effective arterial elastance (Ea). ResultsOver 4 years, Ea was decreased by 3% in tandem with improved blood pressure control, whereas Ees and Eed were increased by 14% and 8% (all, p < 0.001). Greater weight loss over 4 years was associated with progressively greater decreases in Ea in men and women. After adjustment for Ea change, weight gain was correlated with increases in Eed in both women and men. Central obesity was associated with greater age-related increases in Ees in women but not in men, independent of arterial load, but central obesity did not predict changes in Eed or Ea. ConclusionsIn these subjects, weight gain was associated with increases in LV diastolic stiffness, even after adjustment for changes in arterial afterload, whereas weight loss was associated with reductions in arterial stiffness. Age-related LV systolic stiffening was increased in women, but not in men, with central obesity. Strategies for promoting weight loss and reducing central adiposity may be effective in preventing heart failure with preserved ejection fraction, particularly in women.

Abstract 18369: Interleukin-1 Blockade Improves Exercise Capacity in Heart Failure With Preserved Ejection Fraction (HFpEF): Results of the D-HART Study

Treatment options remain limited for patients with heart failure and preserved ejection fraction (HFpEF). Reduced exercise capacity is a common finding in HFpEF. Peak oxygen consumption (peak VO2) represents a gold standard for functional capacity and is a strong independent predictor of adverse outcomes. HFpEF patients also exhibit high levels of systemic inflammation that may be associated with mechanisms of diastolic dysfunction. We enrolled 12 patients with symptomatic HFpEF (LVEF&gt;50% and evidence of abnormal LV relaxation, filling, diastolic distensibility, or diastolic stiffness) and elevated hsCRP (&gt;2 mg/L). Patients were randomized to 14 day crossover treatment with daily subcutaneous injections of IL-1 receptor antagonist (anakinra); 100 mg or matching placebo in a double blind fashion ( NCT01542502 ). The pre-specified primary endpoint was change in peak VO2. Cardiopulmonary exercise testing was performed at baseline and upon completion of each treatment course. We observed a significant improvement in peak VO2 (+1.1 vs -0.1 ml•kg-1•min-1, P=0.009) and the oxygen uptake efficiency slope (+0.23 vs +0.09, P=0.006) and a significant reduction in hsCRP (-84% vs -10%, P=0.006) upon completion of anakinra treatment versus placebo. Correlative studies also revealed significant associations between changes in peak VO2 and hsCRP (R=-0.60, P=0.002). Improvements in ventilator efficiency (VE/VCO2 slope) were limited to patients with above median values for ventilator efficiency (VE/VCO2 slope&gt;26), suggesting that maximum benefits may occur in patients with impaired baseline function. These findings support the hypothesis that systemic inflammation and exercise intolerance in HFpEF are, at least in part, IL-1-dependent and provide the rationale for larger randomized clinical trials to confirm the benefits of IL-1 blockade in patients with HFpEF.

A Cardiovascular Mathematical Model of Graded Head-Up Tilt

A lumped parameter model of the cardiovascular system has been developed and optimized using experimental data obtained from 13 healthy subjects during graded head-up tilt (HUT) from the supine position to . The model includes descriptions of the left and right heart, direct ventricular interaction through the septum and pericardium, the systemic and pulmonary circulations, nonlinear pressure volume relationship of the lower body compartment, arterial and cardiopulmonary baroreceptors, as well as autoregulatory mechanisms. A number of important features, including the separate effects of arterial and cardiopulmonary baroreflexes, and autoregulation in the lower body, as well as diastolic ventricular interaction through the pericardium have been included and tested for their significance. Furthermore, the individual effect of parameter associated with heart failure, including LV and RV contractility, baseline systemic vascular resistance, pulmonary vascular resistance, total blood volume, LV diastolic stiffness and reflex gain on HUT response have also been investigated. Our fitted model compares favorably with our experimental measurements and published literature at a range of tilt angles, in terms of both global and regional hemodynamic variables. Compared to the normal condition, a simulated congestive heart failure condition produced a blunted response to HUT with regards to the percentage changes in cardiac output, stroke volume, end diastolic volume and effector response (i.e., heart contractility, venous unstressed volume, systemic vascular resistance and heart rate) with progressive tilting.

Abstract 9270: Left Ventricular Diastolic Dysfunction is Associated with Increased Vascular Resistance and Reduced VO2max in Patients Awaiting Kidney Transplantation

Hypothesis: Chronic heart failure (CHF) is a major contributor to high mortality in chronic kidney disease (CKD) patients. We hypothesize that LV diastolic stiffness, in part caused by loss of large artery elasticity in CKD, promotes reduction in cardiovascular reserve. Methods: 68 CKD patients (age, 46 ± 13 years; male, 61%) waitlisted for kidney transplantation were prospectively recruited in 2010. TD echocardiography, arterial pulse wave velocity (PWV) and symptom-limited cardiopulmonary exercise testing were performed to determine the relationship between LV diastolic function, arterial stiffness and cardiovascular reserve. Patients were evaluated and categorised into quartile groups according to the level of maximal exercise oxygen capacity (VO2max). Results: Reduced VO2max was significantly associated with higher E/E∋ (p= 0.002). E/E∋ was calculated using the averaged of septal and lateral mitral annular lengthening velocities. A high E/E∋ was also associated with a worse anaerobic threshold (AT) (p&lt;0.001). These patients (with low VO2max and high E/E∋) also demonstrated a significantly greater aortic stiffness (p= 0.026). VO2max was inversely correlated with both E/E∋ (r= -0.413, p= 0.001) and PWV (r= -0.355, p= 0.003). Distribution of gender and history of coronary artery disease were no different between the groups. Conclusions: Evidence for diastolic dysfunction with increased LV filling pressure and diastolic stiffness by the measure of E/E∋ was strongly associated with poor functional cardiovascular reserve. The importance of ventriculo-arterial coupling in the complex mechanism of CKD mediated CHF is evidenced by the significant association between high E/E∋ and increased aortic stiffness.

Abstract 17678: The Correlation Between Collagen Degradation and LV Function Following Induction of Beta-Blocker Therapy

Objectives: Beta-blocker therapy inhibits LV remodeling, and improves not only LV systolic function but also LV diastolic function, and improves prognosis of heart failure patients. But it is unknown why beta-blocker therapy improves LV function. Recently, serum collagen markers such as Procollagen type I C-terminal propeptide (PICP) and collagen type I C-terminal telopeptide (CITP), are useful as index of myocardium collagen synthesis and degradation. We investigate correlation between collagen turnover and LV function following induction of beta-blocker therapy with systolic heart failure patients. Methods: Study population consisted of 46 patients with systolic heart failure. Patients were clinically stable within 1 month and on stable medical therapy, including ACEI or ARB and diuretics, and no beta-blocker therapy. We started beta-blocker therapy, initiated at a target dose of from 5 to 10mg/day. Echocardiography was performed before, 2, 6, and 12 months after the initiation of beta-blocker therapy. LV systolic function was estimated using the LV ejection fraction by Simpson biplane method. Peak systolic strain in the radial direction was measured at the anterior and posterior walls in the short-axis view. We measured E- and A-wave peak velocities and deceleration time (DcT) form the mitral inflow profile, and tissue Doppler early diastolic mitral annular velocity (E'). Serum PICP and CITP were determined. Results (table): A total of 46 patients were enrolled. The median age of all patients was 56±14 years. 15 patients were women and 31 patients were men. EF, DcT and E' were improved after induction of beta-blocker therapy. PICP was not changed, but CITP was decreased from 8.9±7.8 to 6.1±1.7ng/ml at 12 months after treatment. The lower %changes in CITP was associated with the higher %changes in DcT (r=0.21, p&lt;0.05), EF (r=0.29, p&lt;0.01) and radial systolic strain (r=0.26, p&lt;0.05), but not E'. The %changes in PICP were not related %changes in DcT and E'. Conclusions: The improvement in LV systolic function as indexes in EF and radial systolic strain and LV diastolic stiffness as indexes in DcT, correlated with inhibition of collagen degradation in patients with LV systolic function.

Blockage of receptor for advanced glycation end products prevents development of cardiac dysfunction in db/db type 2 diabetic mice

Activation of the receptor for advanced glycation end products (RAGE) is associated with long-term complications in diabetes mellitus. In this study, we tested whether RAGE activation in the diabetic myocardium is implicated in the development of cardiac dysfunction. Using MRI and conductance catheter techniques, we evaluated cardiac function in a type 2 diabetic mouse model (db/db), and assessed the effect of blocking RAGE with a RAGE antibody. Gene expressions were evaluated in samples of myocardial tissue. Diabetic db/db mice demonstrated an accelerated age-dependent deterioration in cardiac function associated with altered expression of genes related to cardiac structure and function. Blockage of RAGE signalling prevented the reduction in systolic function (preload recruitable stroke work: 109.8 +/- 13.8 vs. 94.5 +/- 14.9 mmHg/microL, P = 0.04) and development of increased LV diastolic chamber stiffness (0.18 +/- 0.05 vs. 0.27 +/- 0.07 mmHg, P = 0.01). The cardiac expression of collagen (col1a1) was reduced by approximately 45% and the expression of myosin was switched from the foetal isoform (MHCbeta) to the adult isoform (MHCalpha). Activation of RAGE is a significant pathogenetic mechanism for the development of cardiac dysfunction in type 2 diabetes. The underlying mechanisms involve not only the passive biophysical properties of the myocardium but also myocyte function.

Revisiting Methods for Assessing and Comparing Left Ventricular Diastolic Stiffness

Background: Controversies over the pathophysiology of heart failure with preserved EF have renewed interest in characterization and comparison of LV diastolic stiffness, best assessed using the LV end-diastolic (ED) pressure (P)-volume (V) relationship obtained from multiple beats (MB) during rapid preload reduction. As the MB method is difficult, the diastolic P-V over a single beat with P corrected for effect of ongoing relaxation (RCSB) has been used in human studies but not validated against MB method. Further, the LV stiffness coefficient β in the relation EDP = αeβ∗EDV has been used to compare stiffness, but β covaries with α. This covariance is accounted for by comparing derived EDV at similar EDP, calculated from α, β and EDP of 10, 20 or 30 mmHg (EDV10-30). Objective: Determine if the RCSB method of assessing diastolic stiffness (as quantified by β or EDV10-30) shows good correlation and agreement with the MB method. Methods: P, V were invasively measured and the RCSB followed by MB methods performed in 26 young normal or elderly hypertensive dogs before and during phenylephrine (to vary afterload) or acute volume expansion. In the RCSB method, diastolic P was corrected by subtracting the P due to relaxation, monoexponentially extrapolated from isovolumic relaxation. Correlation was assessed by linear regression. Agreement was expressed as the mean ± SD of the paired difference between MB and RCSB values for β or EDV10-30, expressed as percentages of their mean values; p is for paired t-test. Results: Over widely varying afterloads (LV systolic P 95 to 236 mmHg), EDV10-30 derived from RCSB and MB methods showed excellent correlation (r = 0.98, p < 0.0001) and agreement (0.6 ± 5%, p = 0.6). Correlation (r = 0.62, p = 0.002) and agreement (4.2 ± 45%, p = 0.7) between β from SB and MB was poorer. Use of a limited number of P and V points for the RCSB method (at minimum LV P, pre-atrial contraction, and ED) resulted in less agreement between the methods in assessing EDV10-30 (4.4 ± 9%, p = 0.0003) or β (21 ± 40%, p = 0.025). Neither β (12.5 ± 55%, p = 0.5) nor EDV10-30 (10 ± 10%, p < 0.0001) derived from RCSB agreed with MB after marked volume expansion in presence of pericardium. Conclusion: Clinical studies seeking to compare diastolic stiffness between groups can use the clinically more feasible RCSB to substitute for the complex MB technique under a wide range of afterload. Accuracy will be influenced by the number of P and V points used and by presence of acute volume overload. Comparison of stiffness between groups will be enhanced by methods which account for the covariance between α and β.

Acute and Chronic Ventricular-Arterial Coupling in Systole and Diastole

Aging and hypertension lead to arterial remodeling and tandem increases in arterial (Ea) and ventricular (LV) systolic stiffness (ventricular-arterial [VA] coupling). Age and hypertension also predispose to heart failure with normal ejection fraction (HFnlEF), where symptoms during hypertensive urgencies or exercise are common. We hypothesized that: (1) chronic VA coupling also occurs in diastole, (2) acute changes in Ea are coupled with shifts in the diastolic and systolic pressure-volume relationships (PVR), and (3) diastolic VA coupling reflects changes in LV diastolic stiffness rather than external forces or relaxation. Old chronically hypertensive (OHT, n=8) and young normal (YNL, n=7) dogs underwent assessment of PVR (caval occlusion) and of aortic pressure, dimension, and flow, at baseline and during changes in afterload and preload. Concomitant changes in the slope/position of PVR were accounted for by calculating systolic (ESV(200)) and diastolic (EDV(20)) volumes at common pressures (capacitance). OHT displayed marked vascular remodeling. Indices reflecting the pulsatile component of Ea (aortic stiffness and systemic arterial compliance) were more impaired in OHT at any distending pressure. In both groups, acute increases in Ea were associated with decreases in ESV(200) and EDV(20). However, at any load, OHT had lower ESV(200) and EDV(20), associated with LV remodeling and myocardial endothelin activation. Acute changes in EDV(20) were not mediated by changes in relaxation or external forces. These observations provide insight into the mechanisms whereby arterial remodeling and acute and chronic VA coupling in both systole and diastole may predispose to and interact with increases in load to cause HFnlEF.