Long-term left ventricular echocardiographic follow-up of SHR and WKY rats: effects of hypertension and age

Long-term follow-up of left ventricular (LV) function using echocardiography has not been reported and, in this study, was carried out in normotensive (WKY) rats and spontaneously hypertensive rats (SHR). In 10 WKY rats and SHR, LV diastolic and systolic diameter (LVEDD and LVSD), shortening fraction (SF), and weight (LVW) were determined at 8, 15, 20, 35, and 80 wk of age. The ratio of early to late mitral flow and mitral annulus velocity (VE/VA and Em/Am), isovolumic relaxation time (IVRT), deceleration time of the E wave (DTE), Tei index, and mitral flow propagation velocity (Vp) were measured. No difference in LVEDD was found between SHR and WKY rats; however, LVEDD was increased at 80 wk in both strains. SF decreased slightly in old WKY rats. LVW progressively increased from 20 to 80 wk in both strains and was greater in SHR. VE/VA and Em/Am decreased at 80 wk in WKY rats. LV relaxation (IVRT, Tei index, and Vp) was progressively impaired in SHR compared with WKY rats. LV compliance (DTE) was altered in old SHR. Echocardiography permitted a long follow-up of LV function in SHR and WKY rats. Ventricular relaxation was impaired early in the life of SHR and progressed with aging. Furthermore, LV compliance was altered, but systolic function remained unchanged, in old SHR. In contrast, relaxation and SF were only slightly altered in old WKY rats, suggesting that pressure-related changes in LV function were the dominant features in the SHR.     

Validation of echocardiographic methods for assessing left ventricular dysfunction in rats with myocardial infarction

The rat infarct model is widely used in heart failure research, but few echocardiographic indexes of left ventricular (LV) function are validated in this model. Accordingly, the objective of this study was to validate a 13-segment LV wall motion score index (WMSI) and the myocardial performance index (MPI) in infarcted rats. Twenty-nine male Wistar rats underwent left coronary artery ligation or sham operation and were evaluated with two-dimensional and Doppler flow echocardiography 8 wk later. After echocardiography, invasive indexes were obtained using a high-fidelity catheter. WMSI and MPI were correlated with the invasive and noninvasive measurements of LV function. WMSI and MPI significantly correlated directly with end-diastolic pressure (r=0.72 and 0.42 for WMSI and MPI, respectively) and the time constant of isovolumic relaxation (r=0.68 and 0.48) and inversely with peak rate of rise of LV pressure (+dP/dt; r=-0.68 and -0.50), peak rate of decline in LV pressure (r=-0.57 and -0.44), LV developed pressure (r=-0.58 and -0.42), area fractional shortening (r=-0.85 and -0.53), and cardiac index (r=-0.74 and -0.74). Stepwise linear regression analyses revealed that LV end-diastolic pressure, +dP/dt, area fractional shortening, and cardiac index were independent determinants of WMSI (r=0.994) and that cardiac index and +dP/dt were independent determinants of MPI (r=0.781). We conclude that the 13-segment WMSI and MPI are reproducible and correlate strongly with established echocardiographic and invasive indexes of systolic and diastolic function. These findings support the use of WMSI and MPI as indexes of global LV function in the rat infarction model of heart failure.     

Isovolumic pressure-to-early rapid filling decay rate relation: model-based derivation and validation via simultaneous catheterization echocardiography.

Transmitral Doppler echocardiography is the preferred method of noninvasive diastolic function assessment. Correlations between catheterization-based measures of isovolumic relaxation (IVR) and transmitral, early rapid filling (Doppler E-wave)-derived parameters have been observed, but no model-based, causal explanation has been offered. IVR has also been characterized in terms of its duration as IVR time (IVRT) and by tau, the time-constant of IVR, by approximating the terminal left ventricular IVR pressure contour as Pt= Pinfinity + P(o)e(-t/tau), where Pt is the continuity of pressure, Pinfinity and Po are constants, t is time, and tau is the time constant of IVR. To characterize the relation between IVR and early rapid filling more fully, simultaneous (micromanometric) left ventricular pressure and transmitral Doppler E-wave data from 25 subjects undergoing elective cardiac catheterization and having normal physiology were analyzed. The time constant tau was determined from the dP/dt vs. P (phase) plane and, simultaneous Doppler E-waves provided global indexes of chamber viscosity/relaxation (c), chamber stiffness (k), and load (xo). We hypothesize that temporal continuity of pressure decay at mitral valve opening and physiological constraints permit the algebraic derivation of linear relations relating 1/tau to both peak atrioventricular pressure gradient (kxo) and E-wave-derived viscosity/relaxation (c) but does not support a similar, causal (linear) relation between deceleration time and tau or IVRT. Both predicted linear relations were observed: kxo to 1/tau (r = 0.71) and viscosity/relaxation to 1/tau (r = 0.71). Similarly, as anticipated, only a weak linear correlation between deceleration time and IVRT or tau was observed (r = 0.41). The observed in vivo relationship provides insight into the isovolumic mechanism of relaxation and the changing-volume mechanism of early rapid filling via a link of the respective relaxation properties.     

Diastolic ventricular-vascular stiffness and relaxation relation: elucidation of coupling via pressure phase plane-derived indexes

Because systole and diastole are coupled and systolic ventricular-vascular coupling has been characterized, we hypothesize that diastolic ventricular-vascular coupling (DVVC) exists and can be characterized in terms of relaxation and stiffness. To characterize and elucidate DVVC mechanisms, we introduce time derivative of pressure (dP/dt) vs. time-varying pressure [P(t)] (pressure phase plane, PPP)-derived analogs of ventricular and vascular "stiffness" and relaxation parameters. Although volume change (dV) = 0 during isovolumic periods, and time-varying left ventricular (LV) stiffness, typically expressed as change in pressure per unit change in volume (dP/dV), is undefined, our formulation allows determination of a PPP-derived stiffness analog during isovolumic contraction and relaxation. Similarly, an aortic stiffness analog is also derivable from the PPP. LV relaxation was characterized via tau, the time constant of isovolumic relaxation, and vascular (aortic pressure decay) relaxation was characterized in terms of its equivalent (windkessel) exponential decay time constant kappa. The results show that PPP-derived systolic and diastolic ventricular and vascular stiffness are strongly coupled [K(Ao)(+)=1.71(K(LV)(+)) +154, r=0.86; K(Ao)(-)=0.677(K(LV)(-))-5.53, r=0.86]. In support of the DVVC hypothesis, a strong linear correlation between relaxation (rate of pressure decay) indexes kappa and tau (kappa = 9.89tau - 90.3, r = 0.81) was also observed. The correlations observed underscore the role of long-term, steady-state DVVC as a diastolic function determinant. Awareness of the PPP-derived DVVC parameters provides insight into mechanisms and facilitates quantification of arterial stiffening and associated increase in diastolic chamber stiffness. The PPP method provides a tool for quantitative assessment and determination of the functional coupling of the vasculature to diastolic function.     

MRI assessment of LV relaxation by untwisting rate: a new isovolumic phase measure of tau

Most noninvasive measures of diastolic function are made during left ventricular (LV) filling and are therefore subject to "pseudonormalization," because variation in left atrial (LA) pressure may confound the estimation of relaxation rate. Counterclockwise twist of the LV develops during ejection, but untwisting occurs rapidly during isovolumic relaxation, before mitral opening. We hypothesized that the rate of untwisting might reflect the process of relaxation independent of LA pressure. Recoil rate (RR), the velocity of LV untwisting, was measured by tagged magnetic resonance imaging and regressed against the relaxation time constant (tau), recorded by catheterization, in 10 dogs at baseline and after dobutamine, saline, esmolol, and methoxamine treatment. RR correlated closely (average r = -0.86) with tau and was unaffected by elevated LA pressure. Multiple regression showed that tau, but not LA or aortic pressure, was an independent predictor of RR (P < 0.0001, P = 0.99, and P = 0.18, respectively). The rate of recoil of torsion, determined wholly noninvasively, provides an isovolumic phase, preload-independent assessment of LV relaxation. Use of this novel parameter should allow the detailed study of diastolic function in states known to affect filling rates, such as aging, hypertension, and congestive heart failure.     

Determinants of LV diastolic function during atrial fibrillation: beat-to-beat analysis in acute dog experiments

Left ventricular (LV) diastolic function during atrial fibrillation (AF) remains poorly understood due to the complex interaction of factors and beat-to-beat variability. The purpose of the present study was to elucidate the physiological determinants of beat-to-beat changes in LV diastolic function during AF. The RR intervals preceding a given cardiac beat were measured from the right ventricular electrogram in 12 healthy open-chest mongrel dogs during AF. Doppler echocardiography and LV pressure and volume beat-to-beat analyses were performed. The LV filling time (FT) and early diastolic mitral inflow velocity-time integral (E(vti)) were measured using the pulsed Doppler method. The LV end-diastolic volume (EDV), peak systolic LV pressure (LVP), minimum value of the first derivative of LV pressure curve (dP/dt(min)), and the time constant of LV pressure decay (tau) were evaluated with the use of a conductance catheter for 100 consecutive cardiac cycles. Beat-to-beat analysis revealed a cascade of important causal relations. LV-FT showed a significant positive linear relationship with E(vti) (r = 0.87). Importantly, there was a significant positive linear relationship between the RR interval and LV-EDV in the same cardiac beat (r = 0.53). Consequently, there was a positive linear relationship between LV-EDV and subsequent peak systolic LVP (r = 0.82). Furthermore, there were significant positive linear and negative curvilinear relationships between peak systolic LVP and dP/dt(min) (r = 0.95) and tau (r = -0.85), respectively, in the same cardiac beat. In addition, there was a significant negative curvilinear relationship between dP/dt(min) and tau (r = -0.86). We have concluded that the determinants of LV diastolic function in individual beats during AF depend strongly on the peak systolic LVP. This suggests that the major benefit of slower ventricular rate appears related to lengthening of LV filling interval, promoting subsequent higher peak systolic LVP and greater LV relaxation.     

Ventricular untwisting: a temporal link between left ventricular relaxation and suction

Left ventricular (LV) untwisting starts early during the isovolumic relaxation phase and proceeds throughout the early filling phase, releasing elastic energy stored by the preceding systolic deformation. Data relating untwisting, relaxation, and intraventricular pressure gradients (IVPG), which represent another manifestation of elastic recoil, are sparse. To understand the interaction between LV mechanics and inflow during early diastole, Doppler tissue images (DTI), catheter-derived pressures (apical and basal LV, left atrial, and aortic), and LV volume data were obtained at baseline, during varying pacing modes, and during dobutamine and esmolol infusion in seven closed-chest anesthetized dogs. LV torsion and torsional rate profiles were analyzed from DTI data sets (apical and basal short-axis images) with high temporal resolution (6.5 +/- 0.7 ms). Repeated-measures regression models showed moderately strong correlation of peak LV twisting with peak LV untwisting rate (r = 0.74), as well as correlations of peak LV untwisting rate with the time constant of LV pressure decay (tau, r = -0.66) and IVPG (r = 0.76, P < 0.0001 for all). In a multivariate analysis, peak LV untwisting rate was an independent predictor of tau and IVPG (P < 0.0001, for both). The start of LV untwisting coincided with the beginning of relaxation and preceded suction-aided filling resulting from elastic recoil. Untwisting rate may be a useful marker of diastolic function or even serve as a therapeutic target for improving diastolic function.     

MRI and echocardiographic assessment of the diastolic dysfunction of normal aging: altered LV pressure decline or load?

Changes in diastolic indexes during normal aging, including reduced early filling velocity (E), lengthened E deceleration time (DT), augmented late filling (A), and prolonged isovolumic relaxation time (IVRT), have been attributed to slower left ventricular (LV) pressure (LVP) decay. Indeed, this constellation of findings is often referred to as the "abnormal relaxation" pattern. However, LV filling is determined by the atrioventricular pressure gradient, which depends on both LVP decline and left atrial (LA) pressure (LAP). To assess the relative influence of LVP decline and LAP, we studied 122 normal subjects aged 21-92 yr by Doppler echocardiography and MRI. LVP decline was assessed by color M-mode (V(p)) and the LV untwisting rate. Early diastolic LAP was evaluated using pulmonary vein flow systolic fraction, pulmonary vein flow diastolic DT, color M-mode (E/V(p)), and tissue Doppler (E/E(m)). Linear regression showed the expected reduction of E, increase in A, and prolongation of IVRT and DT with advancing age. There was no relation of age to parameters reflecting the rate of LVP decline. However, older age was associated with reduced E/V(p) (P = 0.008) and increased pulmonary vein systolic fraction (P < 0.001), pulmonary vein DT (P = 0.0026), and E/E(m) (P < 0.0001), all suggesting reduced early LAP. Therefore, reduced early filling in older adults may be more closely related to a reduced early diastolic LAP than to slower LVP decline. This effect also explains the prolonged IVRT. We postulate that changes in LA active or passive properties may contribute to development of the abnormal relaxation pattern during the aging process.     

Effects of modulation of left ventricular contractile state and loading conditions on tissue Doppler myocardial performance index

The Tei index is clinically useful to quantify left ventricular (LV) function, but it requires sequential Doppler recordings from two different views. A related myocardial performance index (MPI) using tissue Doppler (TD) can be rapidly calculated from a single beat; however, its ability to quantify contractility and the effects of acute changes in loading have not been determined. Our aim was to test the hypothesis that TD MPI can quantify contractile state but is affected by acute alterations in loading, using LV pressure-volume relations in an animal model. Eight dogs were studied by using mitral annular TD, high-fidelity pressure, and conductance catheters. TD MPI was calculated as (a' - b')/b', where a' was the duration of mitral annular velocity during diastole and b' was the duration of the systolic wave. End-systolic elastance (Ees), the time constant of isovolumic relaxation (tau), and peak positive and negative first derivative of pressure (dP/dtmax and dP/dtmin, respectively) were used as measures of LV function. Data were obtained at baseline, at dobutamine and esmolol infusion to alter contractile state, and at inferior vena cava and aortic occlusion to alter preload and afterload. TD MPI decreased from 0.83 (SD 0.19) to 0.62 (SD 0.20) with dobutamine and increased to 1.19 (SD 0.26) with esmolol. TD MPI significantly correlated with dP/dtmax (r = -0.76), Ees (r = -0.68), dP/dtmin (r = 0.82), and tau (r = 0.78); however, it was affected by acute decreases in preload [from 0.83 (SD 0.19) to 1.09 (SD 0.36)] and acute increases in afterload [to 1.23 (SD 0.17)]. All the above increases and decreases and r values were significant (P < 0.05 vs. baseline). In conclusion, TD MPI can rapidly quantify alterations in LV contractile state but is affected by acute alterations in preload and afterload.     

Echocardiographic assessment of age-associated changes in systolic and diastolic function of the female F344 rat heart.

Aging is associated with hypertrophy, dilatation, and fibrosis of the left ventricle (LV) of the heart. Advances in echocardiographic assessment have made it possible to follow changes in cardiac function in a serial, noninvasive manner. The purpose was to determine whether there is echocardiographic evidence of age-associated changes in chamber dimensions and systolic and diastolic properties of the female Fischer 344 (F344) rat heart. On the basis of previous invasive studies, it was predicted that echocardiographic assessment would detect age-associated changes in indexes of systolic and diastolic function. Rats were sedated with 1.5% isoflurane and placed in the supine position. Two-dimensional images and two-dimensionally guided M-mode, Doppler M mode, Doppler tissue, and pulsed-wave Doppler recordings were obtained from the parasternal long axis, parasternal short axis, and/or apical four-chamber views as per convention by using a 15-MHz linear array or 8-MHz phased-array transducer or a GE S10-MHz phased-array transducer. Compared with young adult 4-mo-old rats, there is a significant decrement in the resting systolic function of the LV in 30-mo-old female F344 rats as evidenced by declines in LV ejection fraction (80 +/- 9 vs. 89 +/- 5%; mean +/- SD), fractional shortening (43 +/- 9 vs. 54 +/- 8%) and velocity of circumferential fiber shortening (2.43 +/- 0.53 vs. 2.99 +/- 0.50 circ/s). Evidence for age-associated differences in diastolic function included an increase in isovolumic relaxation time (25.0 +/- 7.6 vs. 17.2 +/- 4.4 ms) and decreases in the tissue Doppler peak E waves at the septal annulus and at the lateral annulus of the mitral valve. The modest changes in systolic and diastolic LV function that occur with advancing age in the female F344 rat are likely to reduce the capacity of the heart to respond to hemodynamic challenges.     

Effect of healthy aging on left ventricular relaxation and diastolic suction

Doppler ultrasound measures of left ventricular (LV) active relaxation and diastolic suction are slowed with healthy aging. It is unclear to what extent these changes are related to alterations in intrinsic LV properties and/or cardiovascular loading conditions. Seventy carefully screened individuals (38 female, 32 male) aged 21-77 were recruited into four age groups (young: <35; early middle age: 35-49; late middle age: 50-64 and seniors: ≥65 yr). Pulmonary capillary wedge pressure (PCWP), stroke volume, LV end-diastolic volume, and Doppler measures of LV diastolic filling were collected at multiple loading conditions, including supine baseline, lower body negative pressure to reduce LV filling, and saline infusion to increase LV filling. LV mass, supine PCWP, and heart rate were not affected significantly by aging. Measures of LV relaxation, including isovolumic relaxation time and the time constant of isovolumic pressure decay increased progressively, whereas peak early mitral annular longitudinal velocity decreased with advancing age (P < 0.001). The propagation velocity of early mitral inflow, a noninvasive measure of LV suction, decreased with aging with the greatest reduction in seniors (P < 0.001). Age-related differences in LV relaxation and diastolic suction were not attenuated significantly when PCWP was increased in older subjects or reduced in the younger subjects. There is an early slowing of LV relaxation and diastolic suction beginning in early middle age, with the greatest reduction observed in seniors. Because age-related differences in LV dynamic diastolic filling parameters were not diminished significantly with significant changes in LV loading conditions, a decline in ventricular relaxation is likely responsible for the alterations in LV diastolic filling with senescence.     

Physical determinants of left ventricular isovolumic pressure decline: model prediction with in vivo validation

The rapid decline in pressure during isovolumic relaxation (IVR) is traditionally fit algebraically via two empiric indexes: tau, the time constant of IVR, or tau(L), a logistic time constant. Although these indexes are used for in vivo diastolic function characterization of the same physiological process, their characterization of IVR in the pressure phase plane is strikingly different, and no smooth and continuous transformation between them exists. To avoid the parametric discontinuity between tau and tau(L) and more fully characterize isovolumic relaxation in mechanistic terms, we modeled ventricular IVR kinematically, employing a traditional, lumped relaxation (resistive) and a novel elastic parameter. The model predicts IVR pressure as a function of time as the solution of d(2)P/dt(2) + (1/micro)dP/dt + E(k)P = 0, where micro (ms) is a relaxation rate (resistance) similar to tau or tau(L) and E(k) (1/s(2)) is an elastic (stiffness) parameter (per unit mass). Validation involved analysis of 310 beats (10 consecutive beats for 31 subjects). This model fit the IVR data as well as or better than tau or tau(L) in all cases (average root mean squared error for dP/dt vs. t: 29 mmHg/s for model and 35 and 65 mmHg/s for tau and tau(L), respectively). The solution naturally encompasses tau and tau(L) as parametric limits, and good correlation between tau and 1/microE(k) (tau = 1.15/microE(k) - 11.85; r(2) = 0.96) indicates that isovolumic pressure decline is determined jointly by elastic (E(k)) and resistive (1/mu) parameters. We conclude that pressure decline during IVR is incompletely characterized by resistance (i.e., tau and tau(L)) alone but is determined jointly by elastic (E(k)) and resistive (1/micro) mechanisms.     

Cardiac structural and functional responses to salt loading in SHR

Increased dietary salt intake induces cardiac fibrosis in the spontaneously hypertensive rat (SHR), yet little information details its effects on left ventricular (LV) function. Additionally, young normotensive rats are more sensitive to the trophic effect of dietary sodium than older rats. Thus cardiac responses to salt loading were evaluated at two ages in the SHR; LV collagen content was also examined. SHR (8 or 20 wk of age) were given an 8% salt diet; their age-matched controls received standard chow. Echocardiographic indexes, arterial pressure, and LV hydroxyproline concentration were measured at 16 and 52 wk in the younger and older SHR groups, respectively. In most SHR, salt excess increased arterial pressure, LV mass, and hydroxyproline concentration and impaired LV relaxation manifested by prolonged isovolumic relaxation time, decreased early and atrial filling velocity ratio (V(E)/V(A)), and slower propagation velocity of E wave (V(P)). LV systolic function remained normal. However, one-quarter of the young salt-loaded SHR developed cardiac failure with systolic and diastolic dysfunction associated with greater LV mass and ventricular fibrosis. They also had lower arterial pressure, decreased fractional shortening, and a restrictive pattern of mitral flow. Moreover, the shorter deceleration time of the E wave and increased V(E)/V(P), an index of LV filling pressure, indicated increased LV stiffness in these rats. These findings demonstrated that sodium sensitivity in SHR is manifested not only by further pressure elevation but also by significant LV functional impairment that most likely is related to enhanced ventricular fibrosis. Moreover, the SHR are more susceptible to cardiac damage when high dietary salt is introduced earlier in life.     

Absence of diastolic mitral annular oscillations is a marker for relaxation-related diastolic dysfunction

Although Doppler tissue imaging frequently indicates the presence of mitral annular oscillations (MAO) following the E' wave (E' wave, etc.), only recently was it shown that annular "ringing" follows the rules of damped harmonic oscillatory motion. Oscillatory model-based analysis of E' and E' waves provides longitudinal left ventricular (LV) stiffness (k'), relaxation/viscoelasticity (c'), and stored elastic strain (x(o)') parameters. We tested the hypothesis that presence (MAO(+)) vs. absence (MAO(-)) of diastolic MAO is an index of superior LV relaxation by analyzing simultaneous echocardiographic-hemodynamic data from 35 MAO(+) and 20 MAO(-) normal ejection fraction (EF) subjects undergoing cardiac catheterization. Echocardiographic annular motion and transmitral flow data were analyzed with a previously validated kinematic model of filling. Invasive and noninvasive diastolic function (DF) indexes differentiated between MAO(+) and MAO(-) groups. Specifically, the MAO(+) group had a shorter time constant of isovolumic relaxation [tau; 51 (SD 13) vs. 67 (SD 27) ms; P<0.01] and isovolumic relaxation time [63 (SD 16) vs. 82 (SD 17) ms; P<0.001] and greater ratio of peak E-wave to peak A-wave velocity [1.19 (SD 0.31) vs. 0.97 (SD 0.31); P<0.05]. The MAO(+) group had greater peak lateral mitral annulus velocity [E'; 17.5 (SD 3.1) vs. 13.5 (SD 3.8) cm/s; P<0.001] and LVEF [71.2 (SD 7.5)% vs. 65.4 (SD 9.1)%; P<0.05] and lower heart rate [65 (SD 9) vs. 74 (SD 9) beats/min, P<0.001]. Additional conventional and kinematic modeling-derived indexes were highly concordant with these findings. We conclude that absence of early diastolic MAO is an easily discernible marker for relaxation-related diastolic dysfunction. Quantitation of MAO via stiffness and relaxation/viscoelasticity parameters facilitates quantitative assessment of regional (i.e., longitudinal) DF and may improve diagnosis of diastolic dysfunction.     

Effects of mechanical limitation of apical rotation on left ventricular relaxation and end-diastolic pressure

Left ventricular (LV) twist is thought to play an important role in cardiac function. However, how twist affects systolic or diastolic function is not understood in detail. We acquired apical and basal short-axis images of dogs undergoing open-chest procedures (n = 15) using a GE Vivid 7 at baseline and during the use of an apical suction device (Starfish) to limit apical rotation. We measured LV pressure and stroke volume using a micromanometer-tipped catheter and an ultrasonic flow probe, respectively. Peak radial strain, peak rotation, peak twist, peak systolic twisting rate (TR), peak untwisting rate during isovolumic relaxation period (UR(IVR)), and peak early diastolic untwisting rate after mitral valve opening (UR(E)) were determined using speckle tracking echocardiography. Immobilizing the apex with gentle suction significantly decreased apical rotation (-50 ± 27%) and slightly increased basal rotation, resulting in a significant decrease in twist. The time constant of LV relaxation (τ) was prolonged, and LV end-diastolic pressure increased. TR and UR(IVR) decreased. LV systolic pressure, peak positive and negative first derivative of LV pressure (±dP/dt), stroke volume, radial strain, and UR(E) were not changed. The correlation between τ and UR(IVR) (r = 0.63, P = 0.0006) was stronger than that between peak +dP/dt and TR (r = 0.46, P = 0.01). Diastolic function was impaired with reduced apical rotation and UR(IVR) when the apex of the heart was immobilized using an apical suction device.     

Left ventricular markers of global dyssynchrony predict limited exercise capacity in heart failure, but not in patients with preserved ejection fraction

ABSTRACT: BACKGROUND: The aim of this study was to prospectively examine echocardiographic parameters that correlate and predict functional capacity assessed by 6 min walk test (6-MWT) in patients with heart failure (HF), irrespective of ejection fraction (EF). METHODS: In 147 HF patients (mean age 61 +/- 11 years, 50.3% male), a 6-MWT and an echo-Doppler study were performed in the same day. Global LV dyssynchrony was indirectly assessed by total isovolumic time - t-IVT [in s/min; calculated as: 60 -- (total ejection time + total filling time)], and Tei index (t-IVT/ejection time). Patients were divided into two groups based on the 6-MWT distance (Group I: <=300 m and Group II: >300 m), and also in two groups according to EF (Group A: LVEF >= 45% and Group B: LVEF < 45%). RESULTS: In the cohort of patients as a whole, the 6-MWT correlated with t-IVT (r = -0.49, p < 0.001) and Tei index (r = -0.43, p < 0.001) but not with any of the other clinical or echocardiographic parameters. Group I had lower hemoglobin level (p = 0.02), lower EF (p = 0.003), larger left atrium (p = 0.02), thicker interventricular septum (p = 0.02), lower A wave (p = 0.01) and lateral wall late diastolic myocardial velocity a' (p = 0.047), longer isovolumic relaxation time (r = 0.003) and longer t-IVT (p = 0.03), compared with Group II. In the patients cohort as a whole, only t-IVT ratio [1.257 (1.071-1.476), p = 0.005], LV EF [0.947 (0.903-0.993), p = 0.02], and E/A ratio [0.553 (0.315-0.972), p = 0.04] independently predicted poor 6-MWT performance (<300 m) in multivariate analysis. None of the echocardiographic measurements predicted exercise tolerance in HFpEF. CONCLUSION: In patients with HF, the limited exercise capacity, assessed by 6-MWT, is related mostly to severity of global LV dyssynchrony, more than EF or raised filling pressures. The lack of exercise predictors in HFpEF reflects its multifactorial pathophysiology.     

Coronary collaterals provide a constant scaffold effect on the left ventricle and limit ischemic left ventricular dysfunction in humans

Coronary collaterals preserve left ventricular (LV) function during coronary occlusion by reducing myocardial ischemia and may directly influence LV compliance. We aimed to re-evaluate the relationship between coronary collaterals, measured quantitatively with a pressure wire, and simultaneously recorded LV contractility from conductance catheter data during percutaneous coronary intervention (PCI) in humans. Twenty-five patients with normal LV function awaiting PCI were recruited. Pressure-derived collateral flow index (CFI(p)): CFI(p) = (P(w) - P(v))/(P(a) - P(v)) was calculated from pressure distal to coronary balloon occlusion (P(w)), central venous pressure (P(v)), and aortic pressure (P(a)). CFI(p) was compared with the changes in simultaneously recorded LV end-diastolic pressure (ΔLVEDP), end-diastolic volume, maximum rate of rise in pressure (ΔLVdP/dt(max); systolic function), and time constant of isovolumic relaxation (ΔLV τ; diastolic function), measured by a LV cavity conductance catheter. Measurements were recorded at baseline and following a 1-min coronary occlusion and were duplicated after a 30-min recovery period. There was significant LV diastolic dysfunction following coronary occlusion (ΔLVEDP: +24.5%, P < 0.0001; and ΔLV τ: +20.0%, P < 0.0001), which inversely correlated with CFI(p) (ΔLVEDP vs. CFI(p): r = -0.54, P < 0.0001; ΔLV τ vs. CFI(p): r = -0.46, P = 0.0009). Subjects with fewer collaterals had lower LVEDP at baseline (r = 0.33, P = 0.02). CFI(p) was inversely related to the coronary stenosis pressure gradient at rest (r = -0.31, P = 0.03). Collaterals exert a direct hemodynamic effect on the ventricle and attenuate ischemic LV diastolic dysfunction during coronary occlusion. Vessels with lesions of greater hemodynamic significance have better collateral supply.     

Echocardiographic measurement of cardiac output in rats

The systematic evaluation of different transthoracic echocardiographic (TTE) methods to determine cardiac output (CO) and the effect of changes in intravascular volume on echocardiographically determined indexes of cardiovascular structure in the rat has not been documented. With the use of 11 Wistar rats, simultaneous echocardiographic and thermodilution measurements of CO were compared at baseline and after blood withdrawal or transfusion at 43 different levels of intravascular volume and using 10 different echocardiographic approaches. The best correlation (r = 0.93; P < 0.0001), least bias (-3 ml/min), and best precision (16 ml/min) between thermodilution and echocardiographic methods were obtained at the level of aortic annulus using pulsed Doppler. In conclusion, CO could be accurately assessed in rats using TTE and pulsed Doppler at the level of the aortic annulus. This annulus was demonstrated to remain stable, but pulmonary annulus, thoracic aorta, mitral valve, and left ventricular diameters were found to be more modifiable during volumic changes.     

The onset of left ventricular diastolic dysfunction in SHR rats is not related to hypertrophy or hypertension

Left ventricular (LV) diastolic dysfunction, particularly relaxation abnormalities, are known to be associated with the development of LV hypertrophy (LVH). Preliminary human and animal studies suggested that early LV diastolic dysfunction may be revealed independently of LVH. However, whether LV diastolic dysfunction is compromised before the onset of hypertension and LVH remains unknown. We therefore evaluated LV diastolic function in spontaneously hypertensive rats (SHR) at different ages and tested whether LV diastolic dysfunction is associated with abnormal intracellular calcium homeostasis. LV systolic and diastolic functions were evaluated by invasive and echocardiographic methods in 3-week-old (without hypertension) and 5-week-old (with hypertension) SHR and Wistar-Kyoto control rats. Basal intracytoplasmic calcium and sarcoplasmic reticulum (SR) Ca(2+) contents were measured in cardiomyocytes using fura-2 AM. Sarco(endo)plasmic Ca(2+)-ATPase isoform 2a (SERCA 2a) and phospholamban (PLB) expressions were quantified by Western blot and quantitative RT-PCR techniques. LV relaxation dysfunction was observed in 3-week-old SHR rats before onset of hypertension and LVH. An increase in basal intracytoplasmic Ca(2+) and a decrease in SR Ca(2+) release were demonstrated in SHR. Decreased expression of SERCA 2a and Ser16 PLB (p16-PLB) protein levels was also observed in SHR rats, whereas mRNA expression was not decreased. For the first time, we have shown that LV myocardial dysfunction precedes hypertension in 3-week-old SHR rats. This LV myocardial dysfunction was associated with high diastolic [Ca(2+)](i) possibly due to decreased SERCA 2a and p16-PLB protein levels. Diastolic dysfunction may be a potential predictive marker of arterial hypertension in genetic hypertension syndromes.     

Indexes of diastolic RV function: load dependence and changes after chronic RV pressure overload in lambs

Diastolic function is a major determinant of ventricular performance, especially when loading conditions are altered. We evaluated biventricular diastolic function in lambs and studied possible load dependence of diastolic parameters [minimum first derivative of pressure vs. time (dP/dt(min)) and time constant of isovolumic relaxation (tau)] in normal (n = 5) and chronic right ventricular (RV) pressure-overloaded (n = 5) hearts by using an adjustable band on the pulmonary artery (PAB). Pressure-volume relations were measured during preload reduction to obtain the end-diastolic pressure-volume relationship (EDPVR). In normal lambs, absolute dP/dt(min) and tau were lower in the RV than in the left ventricle whereas the chamber stiffness constant (b) was roughly the same. After PAB, RV tau and dP/dt(min) were significantly higher compared with control. The RV EDPVR indicated impaired diastolic function. During acute pressure reduction, both dP/dt(min) and tau showed a relationship with end-systolic pressure. These relationships could explain the increased dP/dt(min) but not the increased tau-value after banding. Therefore, the increased tau after banding reflects intrinsic myocardial changes. We conclude that after chronic RV pressure overload, RV early relaxation is prolonged and diastolic stiffness is increased, both indicative of impaired diastolic function.