Erina Ghosh

Low-Sodium DASH Diet Improves Diastolic Function and Ventricular–Arterial Coupling in Hypertensive Heart Failure With Preserved Ejection Fraction

Background—Heart failure with preserved ejection fraction (HFPEF) involves failure of cardiovascular reserve in multiple domains. In HFPEF animal models, dietary sodium restriction improves ventricular and vascular stiffness and function. We hypothesized that the sodium-restricted dietary approaches to stop hypertension diet (DASH/SRD) would improve left ventricular diastolic function, arterial elastance, and ventricular–arterial coupling in hypertensive HFPEF. Methods and Results—Thirteen patients with treated hypertension and compensated HFPEF consumed the DASH/SRD (target sodium, 50 mmol/2100 kcal) for 21 days. We measured baseline and post-DASH/SRD brachial and central blood pressure (via radial arterial tonometry) and cardiovascular function with echocardiographic measures (all previously invasively validated). Diastolic function was quantified via the parametrized diastolic filling formalism that yields relaxation/viscoelastic (c) and passive/stiffness (k) constants through the analysis of Doppler mitral inflow velocity (E-wave) contours. Effective arterial elastance (Ea) end-systolic elastance (Ees) and ventricular–arterial coupling (defined as the ratio Ees:Ea) were determined using previously published techniques. Wilcoxon matched-pairs signed-rank tests were used for pre–post comparisons. The DASH/SRD reduced clinic and 24-hour brachial systolic pressure (155±35 to 138±30 and 130±16 to 123±18 mm Hg; both P=0.02), and central end-systolic pressure trended lower (116±18 to 111±16 mm Hg; P=0.12). In conjunction, diastolic function improved (c=24.3±5.3 to 22.7±8.1 g/s; P=0.03; k=252±115 to 170±37 g/s2; P=0.03), Ea decreased (2.0±0.4 to 1.7±0.4 mm Hg/mL; P=0.007), and ventricular–arterial coupling improved (Ees:Ea=1.5±0.3 to 1.7±0.4; P=0.04). Conclusions—In patients with hypertensive HFPEF, the sodium-restricted DASH diet was associated with favorable changes in ventricular diastolic function, arterial elastance, and ventricular–arterial coupling. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00939640.

The vortex formation time to diastolic function relation: assessment of pseudonormalized versus normal filling

In early diastole, the suction pump feature of the left ventricle opens the mitral valve and aspirates atrial blood. The ventricle fills via a blunt profiled cylindrical jet of blood that forms an asymmetric toroidal vortex ring inside the ventricle whose growth has been quantified by the standard (dimensionless) expression for vortex formation time, VFTstandard = {transmitral velocity time integral}/{mitral orifice diameter}. It can differentiate between hearts having distinguishable early transmitral (Doppler E‐wave) filling patterns. An alternative validated expression, VFTkinematic reexpresses VFTstandard by incorporating left heart, near “constant‐volume pump” physiology thereby revealing VFTkinematics explicit dependence on maximum rate of longitudinal chamber expansion (E′). In this work, we show that VFTkinematic can differentiate between hearts having indistinguishable E‐wave patterns, such as pseudonormal (PN; 0.75 < E/A < 1.5 and E/E′ > 8) versus normal. Thirteen age‐matched normal and 12 PN data sets (738 total cardiac cycles), all having normal LVEF, were selected from our Cardiovascular Biophysics Laboratory database. Doppler E‐, lateral annular E′‐waves, and M‐mode data (mitral leaflet separation, chamber dimension) was used to compute VFTstandard and VFTkinematic. VFTstandard did not differentiate between groups (normal [3.58 ± 1.06] vs. PN [4.18 ± 0.79], P = 0.13). In comparison, VFTkinematic for normal (3.15 ± 1.28) versus PN (4.75 ± 1.35) yielded P = 0.006. Hence, the applicability of VFTkinematic for diastolic function quantitation has been broadened to include analysis of PN filling patterns in age‐matched groups.

Determination of early diastolic LV vortex formation time (T∗) via the PDF formalism: A kinematic model of filling

The filling (diastolic) function of the human left ventricle is most commonly assessed by echocardiography, a non-invasive imaging modality. To quantify diastolic function (DF) empiric indices are obtained from the features (height, duration, area) of transmitral flow velocity contour, obtained by echocardiography. The parameterized diastolic filling (PDF) formalism is a kinematic model developed by Kovács et al which incorporates the suction pump attribute of the left ventricle and facilitates DF quantitation by analysis of echocardiographic transmitral flow velocity contours in terms of stiffness (k), relaxation (c) and load (x<inf>o</inf>). A complementary approach developed by Gharib et al, uses fluid mechanics and characterizes DF in terms of vortex formation time (T∗) derived from streamline features formed by the jet of blood aspirated into the ventricle. Both of these methods characterize DF using a causality-based approach. In this paper, we derive T∗s kinematic analogue T∗<inf>kinematic</inf> in terms of k, c and x<inf>o</inf>. A comparison between T∗<inf>kinematic</inf> and T∗<inf>fluid</inf> <inf>mechanic</inf> obtained from averaged transmitral velocity and mitral annulus diameter, is presented. We found that T∗ calculated by the two methods were comparable and T∗<inf>kinematic</inf> correlated with the peak LV recoil driving force kx<inf>o</inf>.

E-wave generated intraventricular diastolic vortex to L-wave relation: model-based prediction with in vivo validation

The Doppler echocardiographic E-wave is generated when the left ventricles suction pump attribute initiates transmitral flow. In some subjects E-waves are accompanied by L-waves, the occurrence of which has been correlated with diastolic dysfunction. The mechanisms for L-wave generation have not been fully elucidated. We propose that the recirculating diastolic intraventricular vortex ring generates L-waves and based on this mechanism, we predict the presence of L-waves in the right ventricle (RV). We imaged intraventricular flow using Doppler echocardiography and phase-contrast magnetic resonance imaging (PC-MRI) in 10 healthy volunteers. L-waves were recorded in all subjects, with highest velocities measured typically 2 cm below the annulus. Fifty-five percent of cardiac cycles (189 of 345) had L-waves. Color M-mode images eliminated mid-diastolic transmitral flow as the cause of the observed L-waves. Three-dimensional intraventricular flow patterns were imaged via PC-MRI and independently validated our hypothesis. Additionally as predicted, L-waves were observed in the RV, by both echocardiography and PC-MRI. The re-entry of the E-wave-generated vortex ring flow through a suitably located echo sample volume can be imaged as the L-wave. These waves are a general feature and a direct consequence of LV and RV diastolic fluid mechanics.

Spatio-temporal attributes of left ventricular pressure decay rate during isovolumic relaxation

Global left ventricular (LV) isovolumic relaxation rate has been characterized: 1) via the time constant of isovolumic relaxation τ or 2) via the logistic time constant τ(L). An alternate kinematic method, characterizes isovolumic relaxation (IVR) in accordance with Newtons Second Law. The models parameters, stiffness E(k), and damping/relaxation μ result from best fit of model-predicted pressure to in vivo data. All three models (exponential, logistic, and kinematic) characterize global relaxation in terms of pressure decay rates. However, IVR is inhomogeneous and anisotropic. Apical and basal LV wall segments untwist at different times and rates, and transmural strain and strain rates differ due to the helically variable pitch of myocytes and sheets. Accordingly, we hypothesized that the exponential model (τ) or kinematic model (μ and E(k)) parameters will elucidate the spatiotemporal variation of IVR rate. Left ventricular pressures in 20 subjects were recorded using a high-fidelity, multipressure transducer (3 cm apart) catheter. Simultaneous, dual-channel pressure data was plotted in the pressure phase-plane (dP/dt vs. P) and τ, μ, and E(k) were computed in 1631 beats (average: 82 beats per subject). Tau differed significantly between the two channels (P < 0.05) in 16 of 20 subjects, whereas μ and E(k) differed significantly (P < 0.05) in all 20 subjects. These results show that quantifying the relaxation rate from data recorded at a single location has limitations. Moreover, kinematic model based analysis allows characterization of restoring (recoil) forces and resistive (crossbridge uncoupling) forces during IVR and their spatio-temporal dependence, thereby elucidating the relative roles of stiffness vs. relaxation as IVR rate determinants.

The quest for load-independent left ventricular chamber properties: Exploring the normalized pressure phase plane

The pressure phase plane (PPP), defined by dP(t)/dt versus P(t) coordinates has revealed novel physiologic relationships not readily obtainable from conventional, time domain analysis of left ventricular pressure (LVP). We extend the methodology by introducing the normalized pressure phase plane (nPPP), defined by 0 ≤ P ≤ 1 and −1 ≤ dP/dt ≤ +1. Normalization eliminates load‐dependent effects facilitating comparison of conserved features of nPPP loops. Hence, insight into load‐invariant systolic and diastolic chamber properties and their coupling to load can be obtained. To demonstrate utility, high‐fidelity P(t) data from 14 subjects (4234 beats) was analyzed. PNR, the nPPP (dimensionless) pressure, where –dP/dtpeak occurs, was 0.61 and had limited variance (7%). The relative load independence of PNR was corroborated by comparison of PPP and nPPP features of normal sinus rhythm (NSR) and (ejecting and nonejecting) premature ventricular contraction (PVC) beats. PVCs had lower P(t)max and lower peak negative and positive dP(t)/dt values versus NSR beats. In the nPPP, +dP/dtpeak occurred at higher (dimensionless) P in PVC beats than in regular beats (0.44 in NSR vs. 0.48 in PVC). However, PNR for PVC versus NSR remained unaltered (PNR = 0.64; P > 0.05). Possible mechanistic explanation includes a (near) load‐independent (constant) ratio of maximum cross‐bridge uncoupling rate to instantaneous wall stress. Hence, nPPP analysis reveals LV properties obscured by load and by conventional temporal P(t) and dP(t)/dt analysis. nPPP identifies chamber properties deserving molecular and cellular physiologic explanation.

Quantitative assessment of left ventricular diastolic function via Longitudinal and Transverse flow impedances

Flow impedance has been used to characterize the physical properties of the vascular system by assessing its phasic flow response to pulsatile pressure input in terms of resistance as a function of frequency. Impedance has also been used to characterize global diastolic left ventricular (LV) chamber properties. In early diastole the LV is a mechanical suction pump and accommodates filling by simultaneously expanding in two principal spatial directions: longitudinal (base-to-apex, long-axis) and transverse (radial, short-axis). Total (characteristic) impedance ZC is the product of longitudinal (ZL) and transverse (ZT) impedance as ZC2=ZLZT where the two impedances reflect the relative spatial propensity for volume accommodation. In this work we compute ZL and ZT for the LV in early diastole. We analyze simultaneously recorded dual pressure-transducer and transthoracic echocardiographic flow data obtained during cardiac catheterization in 11 subjects. We found that ZL was 2 orders of magnitude smaller than ZT in all subjects, providing the first hemodynamic evidence, in concordance with cine-MRI imaging data that longitudinal volume accommodation is indeed, natures preferred spatial filling mechanism. We also investigated the effect of impaired diastolic function on directional impedances and found that ZL increased (becomes worse) while ZT decreased (becomes better) indicating that as diastolic function becomes impaired radial filling compensates for decreased longitudinal volume accommodation to preserve stroke volume. These results provide mechanistic insight and show that normal diastolic function defines a properly impedance matched state and that diastolic dysfunction is equivalent to a state of impedance mismatch.