Relationship of diastolic intraventricular pressure gradients and aerobic capacity in patients with diastolic heart failure

We sought to elucidate the relationship between diastolic intraventricular pressure gradients (IVPG) and exercise tolerance in patients with heart failure using color M-mode Doppler. Diastolic dysfunction has been implicated as a cause of low aerobic potential in patients with heart failure. We previously validated a novel method to evaluate diastolic function that involves noninvasive measurement of IVPG using color M-mode Doppler data. Thirty-one patients with heart failure and 15 normal subjects were recruited. Echocardiograms were performed before and after metabolic treadmill stress testing. Color M-mode Doppler was used to determine the diastolic propagation velocity (Vp) and IVPG off-line. Resting diastolic function indexes including myocardial relaxation velocity, Vp, and E/Vp correlated well with VO2max (r = 0.8, 0.5, and -0.5, respectively, P < 0.001 for all). There was a statistically significant increase in Vp and IVPG in both groups after exercise, but the change in IVPG was higher in normal subjects compared with patients with heart failure (2.6 +/- 0.8 vs. 1.1 +/- 0.8 mmHg, P < 0.05). Increase in IVPG correlated with peak VO2max (r = 0.8, P < 0.001) and was the strongest predictor of exercise capacity. Myocardial relaxation is an important determinant of exercise aerobic capacity. In heart failure patients, impaired myocardial relaxation is associated with reduced diastolic suction force during exercise.     

Estimation of diastolic intraventricular pressure gradients by Doppler M-mode echocardiography

Previous studies have shown that small intraventricular pressure gradients (IVPG) are important for efficient filling of the left ventricle (LV) and as a sensitive marker for ischemia. Unfortunately, there has previously been no way of measuring these noninvasively, severely limiting their research and clinical utility. Color Doppler M-mode (CMM) echocardiography provides a spatiotemporal velocity distribution along the inflow tract throughout diastole, which we hypothesized would allow direct estimation of IVPG by using the Euler equation. Digital CMM images, obtained simultaneously with intracardiac pressure waveforms in six dogs, were processed by numerical differentiation for the Euler equation, then integrated to estimate IVPG and the total (left atrial to left ventricular apex) pressure drop. CMM-derived estimates agreed well with invasive measurements (IVPG: y = 0.87x + 0.22, r = 0.96, P < 0.001, standard error of the estimate = 0.35 mmHg). Quantitative processing of CMM data allows accurate estimation of IVPG and tracking of changes induced by beta-adrenergic stimulation. This novel approach provides unique information on LV filling dynamics in an entirely noninvasive way that has previously not been available for assessment of diastolic filling and function.     

Scaling of diastolic intraventricular pressure gradients is related to filling time duration

In early diastole, pressure is lower in the apex than in the base of the left ventricle (LV). This early intraventricular pressure difference (IVPD) facilitates LV filling. We assessed how LV diastolic IVPD and intraventricular pressure gradient (IVPG), defined as IVPD divided by length, scale to the heart size and other physiological variables. We studied 10 mice, 10 rats, 5 rabbits, 12 dogs, and 21 humans by echocardiography. Color Doppler M-mode data were postprocessed to reconstruct IVPD and IVPG. Normalized LV filling time was calculated by dividing filling time by RR interval. The relationship between IVPD, IVPG, normalized LV filling time, and LV end-diastolic volume (or mass) as fit to the general scaling equation Y = kM beta, where M is LV heart size parameter, Y is a dependent variable, k is a constant, and beta is the power of the scaling exponent. LV mass varied from 0.049 to 194 g, whereas end-diastolic volume varied from 0.011 to 149 ml. The beta values relating normalized LV filling time with LV mass and end-diastolic volume were 0.091 (SD 0.011) and 0.083 (SD 0.009), respectively (P < 0.0001 vs. 0 for both). The beta values relating IVPD with LV mass and end-diastolic volume were similarly significant at 0.271 (SD 0.039) and 0.243 (SD 0.0361), respectively (P < 0.0001 vs. 0 for both). Finally, beta values relating IVPG with LV mass and end-diastolic volume were -0.118 (SD 0.013) and -0.104 (SD 0.011), respectively (P < 0.0001 vs. 0 for both). As a result, there was an inverse relationship between IVPG and normalized LV filling time (r = -0.65, P < 0.001). We conclude that IVPD decrease, while IVPG increase with decreasing animal size. High IVPG in small mammals may be an adaptive mechanism to short filling times.     

Relationship among diastolic intraventricular pressure gradients, relaxation, and preload: impact of age and fitness

Diastolic intraventricular pressure gradients (IVPGs) are a measure of the ability of the ventricle to facilitate its filling using diastolic suction. We assessed 15 healthy young but sedentary subjects, aged <50 yr (young subjects; age, 35 +/- 9 yr); 13 healthy but sedentary seniors, aged >65 yr with known reductions in ventricular compliance (elderly sedentary subjects; age, 70 +/- 4 yr); and 12 master athletes, aged >65 yr, previously shown to have preserved ventricular compliance (elderly fit subjects; age, 68 +/- 3 yr). Pulmonary capillary wedge pressure (PCWP) and echocardiography measurements were performed at baseline, during load manipulation by lower body negative pressure at -15 and -30 mmHg, and after saline infusion of 10 and 20 ml/kg (elderly) or 15 and 30 ml/kg (young). IVPGs were obtained from color M-mode Doppler echocardiograms. Baseline IVPGs were lower (1.2 +/- 0.4 vs. 2.4 +/- 0.7 mmHg, P < 0.0001), and the time constant of pressure decay (tau(0)) was longer (60 +/- 10 vs. 46 +/- 6 ms, P < 0.0001) in elderly sedentary than in young subjects, with no difference in PCWP. Although PCWP changes during load manipulations were similar (P = 0.70), IVPG changes were less prominent in elderly sedentary than in young subjects (P = 0.02). Changes in stroke volume and IVPGs during loading manipulations correlated (r = 0.96, P = 0.0002). PCWP and tau(0) were strong multivariate correlates of IVPGs (P < 0.001, for both). IVPG response to loading interventions in elderly sedentary and elderly fit subjects was similar (P = 0.33), despite known large differences in ventricular compliance. The ability to regulate IVPGs during changes in preload is impaired with aging. Preserving ventricular compliance during aging by lifelong exercise training does not prevent this impairment.     

Computer simulation of intraventricular flow and pressure gradients during diastole

A two-dimensional axisymmetric computer model is developed for the simulation of the filling flow in the left ventricle (LV). The computed results show that vortices are formed during the acceleration phases of the filling waves. During the deceleration phases these are amplified and convected into the ventricle. The ratio of the maximal blood velocity at the mitral valve (peak E velocity) to the flow wave propagation velocity (WPV) of the filling wave is larger than 1. This hemodynamic behavior is also observed in experiments in vitro (Steen and Steen, 1994, Cardiovasc. Res., 28, pp. 1821-1827) and in measurements in vivo with color M-mode Doppler echocardiography (Stugaard et al., 1994, J. Am. Coll. Cardiol., 24, 663-670). Computed intraventricular pressure profiles are similar to observed profiles in a dog heart (Courtois et al., 1988, Circulation, 78, pp. 661-671). The long-term goal of the computer model is to study the predictive value of noninvasive parameters (e.g., velocities measured with Doppler echocardiography) on invasive parameters (e.g., pressures, stiffness of cardiac wall, time constant of relaxation). Here, we show that higher LV stiffness results in a smaller WPV for a given peak E velocity. This result may indicate an inverse relationship between WPV and LV stiffness, suggesting that WPV may be an important noninvasive index to assess LV diastolic stiffness, LV diastolic pressure and thus atrial pressure (preload).     

RV instantaneous intraventricular diastolic pressure and velocity distributions in normal and volume overload awake dog disease models

Intraventricular diastolic right ventricular (RV) flow field dynamics were studied by functional imaging using three-dimensional (3D) real-time echocardiography with sonomicrometry and computational fluid dynamics in seven awake dogs at control with normal wall motion (NWM) and RV volume overload with diastolic paradoxical septal motion. Burgeoning flow cross section between inflow anulus and chamber walls induces a convective pressure rise, which represents a "convective deceleration load" (CDL). High spatiotemporal resolution dynamic pressure and velocity distributions of the intraventricular RV flow field revealed time-dependent, subtle interactions between intraventricular local acceleration and convective pressure gradients. During the E-wave upstroke, the total pressure gradient along intraventricular flow is the algebraic sum of a pressure decrease contributed by local acceleration and a pressure rise contributed by a convective deceleration that partially counterbalances the local acceleration gradient. This underlies the smallness of early diastolic intraventricular gradients. At peak volumetric inflow, local acceleration vanishes and the total adverse intraventricular gradient is convective. During the E-wave downstroke, the strongly adverse gradient embodies the streamwise pressure augmentations from both local and convective decelerations. It induces flow separation and large-scale vortical motions, stronger in NWM. Their dynamic corollaries on intraventricular pressure and velocity distributions were ascertained. In the NWM pattern, the strong ring-like vortex surrounding the central core encroaches on the area available for flow toward the apex. This results in higher linear velocities later in the downstroke of the E wave than at peak inflow rate. The augmentation of CDL by ventriculoannular disproportion may contribute to E wave and E-to-A ratio depression with chamber dilatation.     

Percutaneous balloon mitral valvuloplasty in patients with severe mitral stenosis and low transmitral diastolic pressure gradient

An elevated left atrial pressure and high diastolic pressure gradient (DPG) across the mitral valve are the major hemodynamic abnormalities in mitral stenosis (MS). However, a subgroup of patients with severe MS is characterized by low initial DPG. The authors reviewed the clinical, echocardiographic and hemodynamic data as well as procedural results in 180 patients who underwent percutaneous balloon mitral valvuloplasty (PBMV). An initial mean DPG > 10 mmHg was found in 144 patients (80%) (group A) and mean DPG < or = 10 mmHg in 36 patients (20%) (group B). Patients in group A had higher left ventricular ejection fraction (LVEF) than in group B (61 +/- 5% versus 42 +/- 6%, respectively) and higher cardiac index (2.8 +/- 0.4 versus 2.0 +/- 0.3 l/min/m(2) ). In group B 12 patients (33%) had normal LVEF, whereas 24/36 (67%) had reduced LVEF. All the latter had wall motion abnormalities on ventriculography. Unlike group A, intraprocedural echocardiography was essential for monitoring and evaluating immediate results of PBMV in group B. On follow-up of three years, 75% of group A patients and 55% in group B were in functional class I (p < 0.05). PBMV did not significantly improve symptoms in patients in group B who had preprocedure LVEF < or = 35%.     

Influence of hydrostatic pressure gradients on regulation of plasma volume after exercise

The impact of posture on the immediate recoveryof intravascular fluid and protein after intense exercise wasdetermined in 14 volunteers. Forces which govern fluid and proteinmovement in muscle interstitial fluid pressure(P_ISF), interstitial colloid osmotic pressure (COP_i), andplasma colloid osmotic pressure(COP_p) were measured before andafter exercise in the supine or upright position. During exercise,plasma volume (PV) decreased by 5.7 ± 0.7 and 7.0 ± 0.5 ml/kgbody weight in the supine and upright posture, respectively. Duringrecovery, PV returned to its baseline value within 30 min regardless ofposture. PV fell below this level by 60 and 120 min in the supine andupright posture, respectively (P < 0.05). Maintenance of PV in the upright position was associated with adecrease in systolic blood pressure, an increase inCOP_p (from 25 ± 1 to 27 ± 1 mmHg; P < 0.05), and an increasein P_ISF (from 5 ± 1 to 6 ± 2 mmHg), whereas COP_i wasunchanged. Increased P_ISFindicates that the hydrostatic pressure gradient favors fluid movementinto the vascular space. However, retention of the recaptured fluid inthe plasma is promoted only in the upright posture because of increasedCOP_p.

     

Oxygen pressure gradients in isolated cardiac myocytes

Intracellular oxygen pressure within intact isolated cardiac myocytes is studied as a function of steady state extracellular oxygen pressure. The fractional saturation of myoglobin with oxygen is used to report sarcoplasmic oxygen pressure. The fractional oxidation of cytochrome oxidase, the fractional oxidation of cytochrome c, the rate of respiratory oxygen uptake, and lactate accumulation are used to reflect the availability of oxygen at the inner mitochondrial membrane. These probes of mitochondrial function show no large change with decreasing extracellular oxygen pressure until that pressure is less than 2 torr and intracellular myoglobin is largely deoxygenated. Sarcoplasmic oxygen pressure in resting cells is nearly the same as extracellular oxygen pressure and is about 2 torr less in cells whose respiration has been increased 3.5-fold by mitochondrial uncoupling. Oxygen pressure at the mitochondrial inner membrane differs from sarcoplasmic oxygen pressure by no more than 0.2 torr and from extracellular oxygen pressure by no more than 2 torr. We conclude that differences of oxygen pressure within the cardiac myocyte are very small. This implies that most of the large, about 20 torr, difference in oxygen pressure between capillary lumen and mitochondria of the working heart must be extracellular. We conclude also that mitochondria of the cardiac myocyte become oxygen limited only when sarcoplasmic myoglobin is almost entirely deoxygenated.     

Mineralocorticoid receptor blockade improves diastolic function independent of blood pressure reduction in a transgenic model of RAAS overexpression

There is emerging evidence that aldosterone can promote diastolic dysfunction and cardiac fibrosis independent of blood pressure effects, perhaps through increased oxidative stress and inflammation. Accordingly, this investigation was designed to ascertain if mineralocorticoid receptor blockade improves diastolic dysfunction independently of changes in blood pressure through actions on myocardial oxidative stress and fibrosis. We used young transgenic (mRen2)27 [TG(mRen2)27] rats with increases in both tissue ANG II and circulating aldosterone, which manifests age-related increases in hypertension and cardiac dysfunction. Male TG(mRen2)27 and age-matched Sprague-Dawley rats were treated with either a low dose (～1 mg·kg(-1)·day(-1)) or a vasodilatory, conventional dose (～30 mg·kg(-1)·day(-1)) of spironolactone or placebo for 3 wk. TG(mRen2)27 rats displayed increases in systolic blood pressure and plasma aldosterone levels as well as impairments in left ventricular diastolic relaxation without changes in systolic function on cine MRI. TG(mRen2)27 hearts also displayed hypertrophy (left ventricular weight, cardiomyoctye hypertrophy, and septal wall thickness) as well as fibrosis (interstitial and perivascular). There were increases in oxidative stress in TG(mRen2)27 hearts, as evidenced by increases in NADPH oxidase activity and subunits as well as ROS formation. Low-dose spironolactone had no effect on systolic blood pressure but improved diastolic dysfunction comparable to a conventional dose. Both doses of spironolactone caused comparable reductions in ROS/3-nitrotryosine immunostaining and perivascular and interstitial fibrosis. These data support the notion mineralocorticoid receptor blockade improves diastolic dysfunction through improvements in oxidative stress and fibrosis independent of changes in systolic blood pressure.     

Predictors of outcome after alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy. Special interest for the septal coronary anatomy

Background

Alcohol septal ablation (ASA) provides symptomatic relief in most but not all patients with hypertrophic obstructive cardiomyopathy (HOCM). Therefore we investigated predictors of outcome after ASA.

Methods

Clinical, echocardiographic, angiographic and procedural characteristics were analysed in 113 consecutive patients. Successful ASA was defined as NYHA ≤ 2 with improvement of at least 1 class combined with a resting gradient < 30 mmHg and provoked gradient < 50 mmHg at 4-month follow-up.

Results

In 37 patients ASA was not successful. In multivariate analysis, baseline gradient (OR 1.06 (1.01–1.11) per 5 mmHg, p = 0.024) and distance to the ablated septal branch (OR 1.09 (1.03–1.16) per mm, p = 0.004) were predictors of unsuccessful outcome. The combined presence of a non-ablated septal branch and a distance ≥ 19 mm to the ablated branch was a predictor of unsuccessful outcome (OR 5.88 (2.06–16.7), p < 0.001).

Conclusions

Baseline gradient and a greater distance from the origin of the left anterior descending artery to the ablated septal branch combined with a non-ablated proximal septal branch are associated with an unsuccessful outcome after ASA.     

Latitudinal and depth gradients in marine predation pressure

Aim There is a general paradigm that marine predation pressure increases towards the tropics and decreases with depth. However, data demonstrating global trends are generally lacking. Rhynchonelliform brachiopods inhabit all the oceans and often survive shell‐crushing predator attacks. We investigate shell repair in brachiopods across a range of Southern Hemisphere and tropical Northern Hemisphere latitudes and depths. Location The Southern Hemisphere and tropical Northern Hemisphere. Methods We analysed the frequency of shell repair in 112 bulk samples, over 70% of which showed traces of shell damage and repair. Results The pattern of shell repair frequency (RF) was more complicated than the anticipated increase with decreasing latitude, with low levels at both polar and tropical sites but high levels at temperate latitudes. This pattern is only evident, however, in shallow water assemblages; and there is no latitudinal trend in water depths greater than 200 m, where shell RF is systematically low. There was a significant logarithmic relationship between RF and depth. Low polar repair rates reflect reduced predation pressure, directly supporting the global paradigm. Low rates in the tropics appears counter to the paradigm. However, tropical brachiopods are generally very small (micromorphic) in shallow water and below the minimum size at which damage is recorded anywhere. Main conclusions Predation pressure decreased logarithmically with depth. At shallow depths (< 200 m) RF showed its highest levels in the mid temperate latitudes with decreasing frequency towards both the tropics and the poles. Low levels of shell repair at high latitudes are likely to be due to a lack of crushing predators, but in the tropics it is suggested that the low frequency is a result of the small size of tropical brachiopods. We hypothesize that micromorphy in this region may be an outcome of high predation pressure.     

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.