Time Constant Of Isovolumetric Relaxation Research Articles

Pressure‐based beat‐to‐beat right ventricular ejection fraction and Tau from continuous measured ventricular pressures in COVID‐19 ARDS patients

We evaluated pressure-based right ventricular ejection fraction (RVEF) and diastolic isovolumetric relaxation time constant (Tau) from continuously (up to 30 days) invasive measured right ventricular pressures in mechanically ventilated patients with severe COVID-19 acute respiratory distress syndrome(ARDS). We retrospectively calculated beat-to-beat ejection fraction from right ventricular pressures and dp/dt maximum and minimum in 39 patients treated between October 1st, 2020 and June 30th, 2021. After performing a stepwise logistic regression with survival as a dependent variable, we divided the patients into survivors and nonsurvivors based on their 60-day mortality. Independent outcome variables were the values of RVEF and Tau over time after insertion of the right ventricular probe along with right ventricular systolic and diastolic pressures (RVSP) and the estimated pulmonary artery diastolic pressure (ePAD).RVEF increased significantly over time in the survivors (estimate: 0.354; 95% confidence interval,CI: 0.18-0.53; p < 0.001) but remained unchanged in the nonsurvivors. Tau increased significantly in the nonsurvivors (estimate: 0.001; 95% CI: 0.0004-0.0018; p < 0.002) but not in the survivors. On the last measurement day,RVSP and ePAD were significantly lower while RVEF was significantly higher in the survivors compared to the nonsurvivors. In COVID-19 ARDS patient's, calculation of beat-to-beat RVEF and Tau from continuously invasive measured right ventricular pressures seems to unravel contrary trends in RVEF with an increase in the surviving and a decrease in the nonsurviving patients. Tau remained unchanged in the surviving but increased in the nonsurviving patients over time.

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.

In silico identification of potential calcium dynamics and sarcomere targets for recovering left ventricular function in rat heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a complex disease associated with multiple co-morbidities, where impaired cardiac mechanics are often the end effect. At the cellular level, cardiac mechanics can be pharmacologically manipulated by altering calcium signalling and the sarcomere. However, the link between cellular level modulations and whole organ pump function is incompletely understood. Our goal is to develop and use a multi-scale computational cardiac mechanics model of the obese ZSF1 HFpEF rat to identify important biomechanical mechanisms that underpin impaired cardiac function and to predict how whole-heart mechanical function can be recovered through altering cellular calcium dynamics and/or cellular contraction. The rat heart was modelled using a 3D biventricular biomechanics model. Biomechanics were described by 16 parameters, corresponding to intracellular calcium transient, sarcomere dynamics, cardiac tissue and hemodynamics properties. The model simulated left ventricular (LV) pressure-volume loops that were described by 14 scalar features. We trained a Gaussian process emulator to map the 16 input parameters to each of the 14 outputs. A global sensitivity analysis was performed, and identified calcium dynamics and thin and thick filament kinetics as key determinants of the organ scale pump function. We employed Bayesian history matching to build a model of the ZSF1 rat heart. Next, we recovered the LV function, described by ejection fraction, peak pressure, maximum rate of pressure rise and isovolumetric relaxation time constant. We found that by manipulating calcium, thin and thick filament properties we can recover 34%, 28% and 24% of the LV function in the ZSF1 rat heart, respectively, and 39% if we manipulate all of them together. We demonstrated how a combination of biophysically based models and their derived emulators can be used to identify potential pharmacological targets. We predicted that cardiac function can be best recovered in ZSF1 rats by desensitising the myofilament and reducing the affinity to intracellular calcium concentration and overall prolonging the sarcomere staying in the active force generating state.

Abstract P391: Inhalation Of Airborne Particulate Matter Alters Cardiovascular Function Of Alzheimer-prone Mice

Air pollution has detrimental effects on cardiovascular and lung function, and the extent of its pathological consequences continues to be uncovered. Recently, air pollution has been implicated in the development of Alzheimer Disease (AD) progression. AD and heart failure are common co-morbidities, giving reason to believe that cardiovascular dysfunction may contribute to AD. A known contributor to cardiovascular dysfunction-particulate matter (PM 2.5 , &lt; 2.5 μm diameter)—is a critical component of air pollution and is considered a risk factor for heart failure and AD development. This co-morbidity pattern and shared environmental risk factor prompted the hypothesis that PM 2.5 contributes to cardiovascular dysfunction in a transgenic mouse model of AD. We tested our hypothesis by subjecting 6-month-old transgenic (APP) and non-carrier wildtype (WT) male mice to filtered air (FA) or PM 2.5 for 5 days/week, 6 hours/day for 3 months (n = 34). Following exposure, echocardiography, pressure-volume (PV) loops, and respiratory mechanics were performed to detect cardiac and pulmonary changes associated with genotype and exposure conditions among the 3-month group. Echocardiography revealed left ventricular anterior wall thickness in systole was significantly elevated among PM-exposed APP mice compared to FA-exposed APP controls. PV data demonstrated significant reduced end-systolic elastance in PM-exposed mice compared to FA-exposed mice in both WT and APP mouse models, demonstrating impaired contractility. PV loops also showed that the time constant of isovolumetric relaxation was increased in PM-exposed compared to FA-exposed WT mice. APP mice experienced higher lung resistance and central airway resistance with an increasing dose of methacholine. Taken together, these findings indicate airborne particulate matter exposure causes cardiac and pulmonary dysfunction in a transgenic mouse model of AD.

Hemodynamic Sex‐differences in Diastolic Function

BackgroundIn the past decade, cardiac research has focused on the emerging crisis of diastolic dysfunction, commonly observed in patients with heart failure with preserved ejection fraction (HFpEF) — a disorder with ineffective management strategies. Diastolic dysfunction is abnormal active relaxation and/or passive stiffness of the ventricle. Because echocardiography is non‐invasive and accessible to more specialities, it remains widely used in the diagnosis and prognostic gradation of diastolic dysfunction. However, echocardiography provides indirect estimations of diastolic indices because diastolic measures were calibrated based on direct measures of end diastolic filling pressure (the gold standard for diastolic assessment). As it is increasingly evident that the manifestation of heart failure in men/males and women/females is not the same, a focus on sex‐specific mechanisms and physiology of diastole is warranted.Experimental ApproachThe primary objective of this work is to perform a comprehensive hemodynamic analysis of diastolic function in males and females to highlight sex‐differences that exist in diastolic physiology and provide implications in cardiac pathology. Male and female Wistar rats were anesthetized with isoflurane and a pressure catheter was inserted into the right carotid artery and advanced into the left ventricle. Pressure measurements were sampled at 2kHz and digitized using custom software. Diastolic parameters – end diastolic pressure (EDP), maximum relaxation rate (dP/dtmin), isovolumetric relaxation time constant (Tau Weiss, Glantz, Logistic) – were analyzed to evaluate diastolic function.Results and ConclusionsDiastolic function in healthy males and females is not equal, suggesting there are sex‐specific differences in diastolic physiology. In a pathological state, each of the diastolic parameters follows its own unique time course until severe dysfunction is present, suggesting that diastole cannot be reconciled by any one parameter. EDP, dP/dtmin and Tau Logistic should be used together to stratify dysfunction as diastole is a dynamic process and each parameter captures a specific nuance.Support or Funding InformationCanadian Institutes of Health Research

Long‐term Treatment with Kefir Probiotics Ameliorates Cardiac Function in Spontaneously Hypertensive Rats

We evaluated whether long‐term kefir treatment affects cardiac function (cardiac contractility and calcium‐handling proteins) and sympathetic control in spontaneously hypertensive rats (SHR). Male normotensive rats (WKYs) and SHRs were separated into three groups: SHRs treated with milk fermented by the grains of kefir (5%; SHR‐Kefir; oral gavage, 0.3mL/100g daily/9weeks), and WKYs and SHRs treated with milk. At the end of treatment, direct MAP and HR were measured via artery catheterization. Hemodynamic parameters (left ventricular (LV) systolic pressure (LVSP), left ventricular isovolumetric relaxation time constant (Tau), maximal and minimal pressure decay (+/−dP/dt) were acquired through left ventricular catheter implantation. LV protein expressions of phospholamban (PLB, and phosphorylated (p)‐PBL), and sarcoplasmic reticulum Ca2+‐ATPase (SERCA2a) were determined by Western blot. Tyrosine hydroxylase (TH) protein expression was evaluated via immunofluorescence within the paraventricular nucleus of the hypothalamus (PVN) and rostral ventrolateral medulla (RVLM). We found that the SHR‐Kefir group presented lower MAP (132±0.99mmHg) and HR (321±4.9bpm) compared to SHR (MAP: 167±0.74mmHg; HR: 393±7.3bpm; P&lt;0.01). Kefir ameliorated cardiac hypertrophy (LV weight/body weight ratio: WKY, 1.006±0.04; SHR, 1.900±0.09; SHR‐Kefir; 1.488±0.09mg/g; P&lt;0.05) and promoted reduced expression of PBL (WKY, 100%; SHR, 143.5±19.9%; SHR‐Kefir, 112.2±10.7%), p‐PBL (WKY, 100%; SHR, 127.2±8.9%; SHR‐Kefir, 101.4±10.3%), and SERCA2a (WKY, 100%; SHR, 134.3±7.8%; 69.2±16%; P&lt;0.05) contractile proteins. Within the PVN and RVML, TH protein overexpression observed in SHRs was reduced by kefir treatment (PVN: WKY, 7.42±0.8; SHR, 14.2±0.8; SHR‐Kefir, 8.1±0.7, and RVLM: WKY, 1.39±0.05; SHR, 1.7±0.13; SHR‐Kefir, 1.2±0.09 arbitrary units). In addition, kefir treatment improved cardiac hemodynamic parameters in SHR, including: LVSP (WKY, 115.5±1.2; SHR, 172.2±1.1; SHR‐Kefir, 137.01±1.2 mmHg; P&lt;0.01, Tau (WKY, 0.046±0.003; SHR, 0.027±0.0007; SHR‐Kefir, 0.04±0.001 s; P&lt;0.05), +dP/dt (WKY, 3021±53.5; SHR, 4926±46.5 ; SHR‐Kefir, 3955±32.5 mmHg/sec; P&lt;0.01), and ‐dP/dt (WKY, −3241±313.2; SHR, −4151±81.9; SHR‐Kefir, −2705±41.8 mmHg/sec; P&lt;0.01). Altogether, our data show that long‐term kefir treatment reduced blood pressure by mechanisms involving reduction of cardiac hypertrophy, ameliorating cardiac function by improvement of cardiac contractility and calcium‐handling proteins, and a reduction in the CNS regulation of the sympathetic activity.Support or Funding InformationWork supported by CAPES; Finance Code 001, BRA, and FAPES 0279/2016.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Long-term treatment with kefir probiotics ameliorates cardiac function in spontaneously hypertensive rats

This work evaluated the effects of long-term kefir treatment in cardiac function (cardiac contractility and calcium-handling proteins) and the central nervous system (CNS) control of the sympathetic signaling in spontaneously hypertensive rats (SHR). Male normotensive rats [Wistar Kyoto rats (WKYs)] and SHRs were divided into three groups: WKYs and SHRs treated with vehicle, and SHRs treated with milk fermented by the grains of kefir (5%; SHR-Kefir; oral gavage, 0.3 ml/100 g daily/9 weeks). At the end of treatment, mean arterial pressure (MAP) and heart rate (HR) were measured by direct arterial catheterization. Hemodynamic parameters (left ventricular systolic pressure, left ventricular isovolumetric relaxation time constant, maximal and minimal pressure decay) were acquired through a left ventricular catheter implantation. Left ventricle protein expressions of phospholamban (PLB), its phosphorylated form (p-PLB) and sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) were determined by Western blot. Tyrosine hydroxylase (TH) protein expression was evaluated via immunofluorescence within the paraventricular nucleus (PVN) of the hypothalamus and the rostral ventrolateral medulla (RVLM). SHR-Kefir group presented lower MAP and HR compared to SHRs. Kefir treatment ameliorated cardiac hypertrophy and promoted reduced expression of PLB, p-PLB and SERCA2a contractile proteins. Within the PVN and RVML, TH protein overexpression observed in SHRs was reduced by probiotic treatment. In addition, kefir improved cardiac hemodynamic parameters in SHR-treated animals. Altogether, the data show that long-term kefir treatment reduced blood pressure by mechanisms involving reduction of cardiac hypertrophy, improvement of cardiac contractility and calcium-handling proteins, and reduction in the CNS regulation of the sympathetic activity.

A mouse model of heart failure with preserved ejection fraction due to chronic infusion of a low subpressor dose of angiotensin II.

Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome of HF symptoms associated with impaired diastolic function. Although it represents ∼50% of patients with HF, the mechanisms of disease are poorly understood, and therapies are generally ineffective in reducing HF progression. Animal models of HFpEF not due to pressure or volume overload are lacking, therefore limiting in-depth understanding of the pathophysiological mechanisms and the development of novel therapies. We hypothesize that a continuous infusion of low-dose angiotensin II (ATII) is sufficient to induce left ventricular (LV) diastolic dysfunction and HFpEF, without increasing blood pressure or inducing LV hypertrophy or dilatation. Osmotic pumps were implanted subcutaneously in 8-wk-old male mice assigned to the ATII (0.2 mg·kg(-1)·day(-1)) or volume-matched vehicle (N = 8/group) for 4 wk. We measured systolic and diastolic arterial blood pressures through a tail-cuff transducer, LV dimensions and ejection fraction through echocardiography, and LV relaxation through pulsed-wave Doppler and LV catheterization. Myocardial fibrosis and cardiomyocyte cross-sectional area were measured. ATII infusion had no effects on systemic arterial blood pressure. ATII induced significant impairment in LV diastolic function, as measured by an increase (worsening) in LV isovolumetric relaxation time, myocardial performance index, isovolumetric relaxation time constant, and LV end-diastolic pressure without altering LV dimensions, mass, or ejection fraction. Chronic infusion of low-dose ATII recapitulates the HFpEF phenotype in the mouse, without increasing systemic arterial blood pressure. This mouse model may provide insight into the mechanisms of HFpEF.

Esmolol added in repeated, cold, oxygenated blood cardioplegia improves myocardial function after cardiopulmonary bypass.

This study investigated if the β-receptor blocking agent esmolol, added to standard oxygenated blood cardioplegia, improved myocardial function after weaning from bypass. A block-randomized, blinded study. A university laboratory. Twenty anesthetized pigs, Norwegian Landrace. After cardiopulmonary bypass, cardiac arrest was induced with cold (12°C), oxygenated blood cardioplegia, enriched with either esmolol or vehicle, repeated every 20 minutes. After 100 minutes the heart was reperfused and weaned. Left ventricular function was evaluated with pressure-volume loops, local myocardial function with multilayer strain and strain rate by epicardial short-axis tissue Doppler imaging. One hour after declamping, preload recruitable stroke work did not differ between groups, but increased to 72±3 mmHg in esmolol-treated animals v 57±4 mmHg (p<0.001) in controls after 3 hours. Radial peak ejection strain rate also was increased by esmolol; 6.0±1.0 s(-1)v 2.9±0.3 s(-1) (p<0.001) in subendocardium and 3.9±0.5 s(-1)v 2.3±0.2 s(-1) (p<0.005) in the midmyocardium. Cardiac index was increased, 4.0±0.2 L/min/m(2) by esmolol v 3.3±0.1 L/min/m(2) for controls (p<0.05). Isovolumetric relaxation time constant was reduced by esmolol, 23±1 ms v 26±1 ms (p<0.025). Troponin-T did not differ and was 339±48 ng/L for the esmolol group and 357±55 ng/L for the control group (p = 0.81). Esmolol added to blood cardioplegia preserved systolic cardiac function during the first 3 hours after reperfusion in a porcine model with 100 minutes of cardioplegic arrest.

Regional wall motion abnormality at the lateral wall disturbs correlations between tissue Doppler E/e′ ratios and left ventricular diastolic performance parameters measured by invasive methods

BackgroundThe impact of regional wall motion abnormality (RWMA) on the accuracy of heart failure with preserved ejection fraction (HFpEF) diagnosis using the E/e′ ratio, which is a non-invasive parameter of left ventricular diastolic performance, is unknown. The purpose of this study was to elucidate the impact of RWMA of the lateral wall (RWMAlat) on the correlation between E/e′ and invasive parameters of left ventricular diastolic performance.MethodsThree hundred and eight consecutive patients undergoing tissue Doppler imaging and catheterization pressure examination were retrospectively analyzed. E/e′ was calculated as the ratio of early diastolic transmitral flow velocity to mitral annular velocity at the lateral wall. Invasive parameters including left ventricular end-diastolic pressure (LVEDP) and isovolumetric relaxation time constant (τ) were assessed based on the left ventricular pressure study. Correlation coefficients between E/e′ and these invasive parameters were analyzed and compared between cases with RWMAlat and without RWMA.ResultsLVEDP and τ correlated well with E/e′ for all 308 patients (r = 0.51 and r = 0.65, respectively). Sixty-two patients had RWMA; the remaining 246 did not have RWMAlat. We confirmed that the presence of RWMAlat weakens both the correlations between E/e′ and LVEDP (r = 0.574 vs. r = 0.381), and E/e′ and τ (r = 0.729 vs. r = 0.461).ConclusionsAlthough E/e′ correlates well with parameters of left ventricular diastolic performance assessed by invasive methods, the presence of RWMAlat worsens this correlation. In cases with RWMAlat, careful assessment is required for HFpEF diagnosis because the diagnostic value of the E/e′ ratio could be decreased compared to patients without RWMAlat.

Lipid Lowering and HDL Raising Gene Transfer Increase Endothelial Progenitor Cells, Enhance Myocardial Vascularity, and Improve Diastolic Function

BackgroundHypercholesterolemia and low high density lipoprotein (HDL) cholesterol contribute to coronary heart disease but little is known about their direct effects on myocardial function. Low HDL and raised non-HDL cholesterol levels carried increased risk for heart failure development in the Framingham study, independent of any association with myocardial infarction. The objective of this study was to test the hypothesis that increased endothelial progenitor cell (EPC) number and function after lipid lowering or HDL raising gene transfer in C57BL/6 low density lipoprotein receptor deficient (LDLr−/−) mice may be associated with an enhanced relative vascularity in the myocardium and an improved cardiac function.Methodology/principal findingsLipid lowering and HDL raising gene transfer were performed using the E1E3E4-deleted LDLr expressing adenoviral vector AdLDLr and the human apolipoprotein A-I expressing vector AdA-I, respectively. AdLDLr transfer in C57BL/6 LDLr−/− mice resulted in a 2.0-fold (p<0.05) increase of the circulating number of EPCs and in an improvement of EPC function as assessed by ex vivo EPC migration and EPC adhesion. Capillary density and relative vascularity in the myocardium were 28% (p<0.01) and 22% (p<0.05) higher, respectively, in AdLDLr mice compared to control mice. The peak rate of isovolumetric relaxation was increased by 12% (p<0.05) and the time constant of isovolumetric relaxation was decreased by 14% (p<0.05) after AdLDLr transfer. Similarly, HDL raising gene transfer increased EPC number and function and raised both capillary density and relative vascularity in the myocardium by 24% (p<0.05). The peak rate of isovolumetric relaxation was increased by 16% (p<0.05) in AdA-I mice compared to control mice.Conclusions/SignificanceBoth lipid lowering and HDL raising gene transfer have beneficial effects on EPC biology, relative myocardial vascularity, and diastolic function. These findings raise concerns over the external validity of studies evaluating myocardial biology and cardiac repair in normocholesterolemic animals.

Cardiac function during mild hypothermia in pigs: increased inotropy at the expense of diastolic dysfunction

The induction of mild hypothermia (MH; 33 degrees C) has become the guideline therapy to attenuate hypoxic brain injury after out-of-hospital cardiopulmonary resuscitation. While MH exerts a positive inotropic effect in vitro, MH reduces cardiac output in vivo and is thus discussed critically when severe cardiac dysfunction is present in patients. We thus assessed the effect of MH on the function of the normal heart in an in vivo model closely mimicking the clinical setting. Ten anaesthetized, female human-sized pigs were acutely catheterized for measurement of pressure-volume loops (conductance catheter), cardiac output (Swan-Ganz catheter) and for vena cava inferior occlusion. Controlled MH (from 37 to 33 degrees C) was induced by a vena cava inferior cooling catheter. With MH, heart rate (HR) and whole body oxygen consumption decreased, while lactate levels remained normal. Cardiac output, left ventricular (LV) volumes, peak systolic and end-diastolic pressure and dP/dt(max) did not change significantly. Changes in dP/dt(min) and the time constant of isovolumetric relaxation demonstrated impaired active relaxation. In addition, MH prolonged the systolic and shortened the diastolic time interval. Pressure-volume analysis revealed increased end-systolic and end-diastolic stiffness, indicating positive inotropy and reduced end-diastolic distensibility. Positive inotropy was preserved during pacing, while LV end-diastolic pressure increased and diastolic filling was substantially impaired due to delayed LV relaxation. MH negatively affects diastolic function, which, however, is compensated for by decreased spontaneous HR. Positive inotropy and a decrease in whole body oxygen consumption warrant further studies addressing the potential benefit of MH on the acutely failing heart.

Effect of hypertrophy on left ventricular diastolic function in patients with hypertrophic cardiomyopathy

Background.Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric LV hypertrophy (LVH) and impairment in diastolic function. We assess the relationship between LVH and invasive indexes of diastolic function.Methods.21 HCM patients underwent cardiac catheterization to assess pulmonary capillary wedge pressure, LV end-diastolic pressure (measured by microtip catheters), and LV volumes (calculated by simultaneous radionuclide angiography). We calculated from LV pressure the time constant of isovolumetric relaxation (τ, variable asymptote method, ms), and from LV pressure and volume the constant of chamber stiffness (k, ml−1). LVH was assessed by different indexes: maximal wall thickness, number of hypertrophied LV segments, LVH index, and Wigle’s score. Results. Wigle’s score was directly related to pulmonary capillary Wedge pressure (r=0.436, p=0.048), peak V wave of pulmonary capillary wedge pressure (r=0.503, p=0.024), LV end-diastolic pressure (r=0.643, p=0.002) and k (r=0.564, p=0.015). HCM patients were divided into 2 groups according to Wigle’s score: 10 with mild or moderate LVH (< 8), and 11 with severe LVH (≥ 8). HCM patients with severe LVH showed a higher pulmonary capillary Wedge pressure (15.1±7.2 vs 9.5±2.4, p=0.033), peak V wave of pulmonary capillary wedge pressure (20.7±4.6 vs 14.6±4.9, p=0.011), LV end-diastolic pressure (23.9±10.9 vs 10.6±2.5, p=0.002), k (0.0465±0.032 vs 0.015±0.007, p=0.022) and LV outflow tract gradient (72±36 mmHg vs 29±30 mmHg, p=0.01).τ was similar in the two groups. Other indexes of LVH were not related to diastolic function.Conclusions.Wigle’s score is the only index of LVH that relates to invasive indices of diastolic function.

Assessment of the time constant of relaxation: insights from simulations and hemodynamic measurements.

The objective of this study was to use high-fidelity animal data and numerical simulations to gain more insight into the reliability of the estimated relaxation constant derived from left ventricular pressure decays, assuming a monoexponential model with either a fixed zero or free moving pressure asymptote. Comparison of the experimental data with the results of the simulations demonstrated a trade off between the fixed zero and the free moving asymptote approach. The latter method more closely fits the pressure curves and has the advantage of producing an extra coefficient with potential diagnostic information. On the other hand, this method suffers from larger standard errors on the estimated coefficients. The method with fixed zero asymptote produces values of the time constant of isovolumetric relaxation (tau) within a narrow confidence interval. However, if the pressure curve is actually decaying to a nonzero pressure asymptote, this method results in an inferior fit of the pressure curve and a biased estimation of tau.

Preconditioning with cromakalim improves long-term myocardial preservation for heart transplantation

Background. Myocardial preservation for heart transplantation relies on hyperkalemic cardiac arrest and hypothermic storage. Our study investigated whether pretreatment with a potassium-channel opener (cromakalim) before prolonged storage in an extracellular fluid improves left ventricular recovery. Methods. Rabbit hearts were submitted to 6-hours’ cold storage and assessed on a blood-perfused isolated heart preparation. Hemodynamic recovery, enzyme release (creatine kinase and lactate dehydrogenase), and adenine nucleotide content were determined. Five groups were tested: control (n = 6), no ischemia; UW group (n = 7), hearts arrested with and stored in University of Wisconsin solution; STH group (n = 5), hearts arrested with and stored in St. Thomas’ Hospital solution; cromakalim group (n = 6), hearts pretreated with cromakalim (30 μg/kg) before arrest with and storage in St. Thomas’ Hospital solution; and glibenclamide group (n = 5), hearts pretreated with cromakalim followed by glibenclamide (a potassium-channel blocker) before arrest with and storage in St. Thomas’ Hospital solution. Results. Hemodynamic recovery was improved and enzyme release was lower in the UW group than in the STH group. Compared with the STH group, the group pretreated with cromakalim had significantly decreased left ventricular end-diastolic pressures, increased left ventricular developed pressures, increased maximal values of positive and negative rates of rise of left ventricular pressure, and increased time constant of isovolumetric relaxation. Hemodynamic recovery was similar in the UW group and cromakalim groups. Glibenclamide did not abolish the effects of cromakalim. None of the protocols affected myocardial energy stores. Conclusions. Pretreatment with cromakalim affords additional protection to that provided by cardioplegic arrest and prolonged cold storage using an extracellular solution. The intracellular mechanisms involved remain to be determined.

Effects of platelet-activating factor on left ventricular performance in dogs.

To elucidate the mechanism by which platelet-activating factor (PAF) decreases cardiac output (CO), its effects on left ventricular (LV) performance were studied using a LV pressure-volume model in 9 anesthetized dogs. LV volume was measured with a conductance catheter and LV pressure with a manometer-tipped catheter. The slopes of the end-systolic pressure-volume (Ees), stroke work-end-diastolic volume (Mw), and arterial end-systolic pressure-stroke volume relations (Ea), and of end-diastolic pressure-volume relations (EDPVRs), were obtained to evaluate changes in LV performance. The time constant of isovolumetric relaxation (T) was computed by a logarithmic and a derivative method. After intravenous administration of PAF (1 microgram/kg), LV end-diastolic volume and pressure, end-systolic pressure, maximum dP/dt and CO decreased. Ees and Mw decreased significantly, minimum dP/dt decreased, and T increased. The arterial end-systolic pressure-stroke volume relation shifted leftward with an increase in the slope (Ea), whereas EDPVRs were shifted to the left and superimposed on their potential passive diastolic properties. These findings indicate the PAF decreases CO by reducing preload and contractility and by increasing arterial load. However, despite a prolongation of relaxation, PAF may not affect passive diastolic chamber stiffness.

Effects of Diltiazem on Left Ventricular Systolic and Diastolic Function in Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HC) is characterized by impaired diastolic function, and left ventricular (LV) out-flow tract obstruction in about one-fourth of patients. Verapamil improves diastolic properties, but may have dangerous adverse effects. This study investigates the effects of diltiazem on hemodynamics and LV function in 16 patients with HC who were studied with cardiac catheterization and simultaneous radionuclide angiography. Studies were performed during atrial pacing (15 beats above spontaneous rhythm) at baseline and during intravenous diltiazem administration (0.25 mg·kg −1 over 2 minutes, and 0.014 mg·kg −1·min −1). Diltiazem induced a systemic vasodilation (cardiac index: 3.4 ± 1.0 to 4.0 ± 1.0 L·min −1·m −2, p = 0.003; aortic systolic pressure: 116 ± 16 to 107 ± 19 mm Hg, p = 0.007; systemic resistance index: 676 ± 235 to 532 ± 193 dynes·s·cm −5·m −2, p = 0.006), not associated with changes in the LV outflow tract gradient. The end-systolic pressure/volume ratio decreased (30 ± 42 to 21 ± 29 mm Hg·ml −1·m −2; p = 0.044). Pulmonary artery wedge pressure (11 ± 5 to 15 ± 6 mm Hg, p = 0.006), and peak filling rate increased (4.1 ± 1.3 to 6.0 ± 2.4 stroke counts·s −1, p = 0.004). The time constant of iso-volumetric relaxation τ decreased (74 ± 40 to 59 ± 38 ms, p = 0.045). The constant of LV chamber stiffness did not change. Thus, active diastolic function is improved by the acute administration of diltiazem by both direct action and changes in hemodynamics and loading conditions. LV outflow tract gradient does not increase despite systemic vasodilation. In some patients, however, a marked increase in obstruction and a potentially harmful elevation in pulmonary artery wedge pressure do occur. Passive diastolic function is not affected. (Am J Cardiol 1996;78:451–457)

Effects of dual-chamber pacing in hypertrophic cardiomyopathy on left ventricular outflow tract obstruction and on diastolic function

Hypertrophic cardiomyopathy (HC) is characterized by impaired diastolic function and, in about 1 4 of patients, left ventricular (LV) outflow tract obstruction. Atrioventricular (AV) pacing diminishes LV outflow tract gradient in HC, but impairs diastolic function in the experimental animal and in different categories of patients. To investigate the effects of AV pacing on hemodynamics and LV function in obstructive HC, 16 patients with HC were studied by cardiac catheterization and simultaneous radionuclide angiography during atrial and AV pacing. The resting LV outflow tract gradient decreased with AV pacing from 60 ± 34 to 38 ± 37 mm Hg (mean ± SD; p < 0.001). Regional ejection fraction decreased significantly at the septal level, from 0.81 ± 0.21% to 0.69 ± 0.27% (p < 0.01). Pulmonary artery wedge pressure increased from 10 ± 5 to 15 ± 6 mm Hg (p < 0.001). AV pacing induced asynchrony (i.e., the coefficient of variation of the time to end-systole increased from 7 ± 4% to 14 ± 10% (p < 0.01). The time constant of isovolumetric relaxation (τ) increased from 58 ± 24 to 74 ± 33 ms (p < 0.02), and peak filling rate decreased from 491 ± 221 to 416 ± 184 ml/s (p < 0.05). Thus, AV pacing greatly diminishes resting obstruction through a reduction in septal ejection fraction (i.e., an increase in LV outflow tract width in systole), but impairs active diastolic function and increases filling pressures. These latter effects are potentially detrimental in patients with HC in whom diastolic dysfunction is present.

Comparison of the alteration of cardiac function by sevoflurane, isoflurane, and halothane in the isolated working rat heart

Despite its widespread use, little is known about sevoflurane's physiologic effects. The direct myocardial effects of sevoflurane were compared with both halothane and isoflurane. Administration of minimum alveolar concentration (MAC) fractions of anesthetic (0 to 3.0) was systematically varied to decrease the possibility of time-related effects on measured parameters. Isolated rat hearts were perfused using a working heart model where the parameters affecting myocardial work were carefully controlled and monitored. To avoid confounding effects of prior anesthetic administration, hearts were removed from rats, after decapitation, in the absence of anesthetic. In the first series, isolated perfused rat hearts were exposed to one of the three anesthetics in doses of 0 to 1.5 times MAC. In the second series, hearts were exposed to either sevoflurane or isoflurane in doses of 0 to 3.0 times MAC. The following variables were measured: the rate of change of left ventricular pressure; aortic flow rate; cardiac output; left ventricular end-diastolic pressure; the time constant of isovolumetric relaxation; and coronary vascular resistance. Oxygen consumption was measured during the first series. In the first series, all systolic variables were reduced in the presence of halothane when compared with either isoflurane or sevoflurane. Halothane affected diastolic function to a greater degree than either sevoflurane or isoflurane, as measured by the rate of relaxation and end-diastolic pressure. In the second series, at a dose of 3.0 times MAC, both sevoflurane and isoflurane decreased systolic and diastolic function, with a greater reduction in cardiac output, and peak aortic flow and higher left ventricular end-diastolic pressures observed with isoflurane. Coronary resistance and oxygen consumption were not affected by any of the anesthetics. These data suggest that sevoflurane depresses cardiac function less than either halothane in doses of 1.0 and 1.5 x MAC or isoflurane at doses of 3 x MAC.

Differential effects of dobutamine and a phosphodiesterase inhibitor on early diastolic filling in patients with congestive heart failure

Objectives. This study was designed to compare the influence of beta-adrenergic stimulation (dobutamine) and a selective phosphodiesterase inhibitor (MS-857) on left ventricular diastolic performance and Doppler transmitral flow velocity patterns in patients with congestive heart failure and to elucidate the mechanisms for changes in early diastolic filling induced by each agent.Background. Both beta-adrenergic agonists and phosphodiesterase inhibitors act through the cyclic adenosine monophosphate pathway. However, it is controversial whether they have similar effects on diastolic performance. No previous studies have investigated the effects of these agents on Doppler-derived measurements of diastolic filling. We hypothesized that they would have different effects on early diastolic filling in patients with congestive heart failure.Methods. Twenty patients with chronic congestive heart failure resulting from idiopathic dilated cardiomyopathy were randomized to receive intravenous infusion of dobutamine (5 μg/kg body weight per min, n = 10) or oral administration of MS-857 (15 mg, n = 10). Transmitral flow velocity patterns were obtained with simultaneous recordings of pressure-volume loops using a conductance catheter with a micromanometer tip before and after drug administration.Results. Left ventricular filling pressure was reduced by both agents. Dobutamine decreased the time constant of isovolumetric relaxation and increased the difference between pulmonary artery wedge pressure at the peak of the vwave and left ventricular minimal pressure (10 ± 3 to 12 ± 4 mm Hg, p < 0.01) and peak early filling velocity (47 ± 7 to 56 ± 11 cm/s, p < 0.01). The diastolic pressure-volume relation showed a leftward shift in all patients. In contrast, MS-857 did not affect the time constant but maintained the pressure difference (9 ± 3 to 8 ± 3 mm Hg, p = NS) and peak early filling velocity (50 ± 7 to 49 ± 12 cm/s, p = NS). The diastolic pressure-volume relation after MS-857 showed a downward shift in most patients.Conclusions. These results indicate that beta-adrenergic stimulation and phosphodiesterase inhibitors have different effects on early diastolic filling through different mechanisms in patients with congestive heart failure.