M. Mar Desco

A Noninvasive Method for Assessing Impaired Diastolic Suction in Patients With Dilated Cardiomyopathy

Background— Diastolic suction is a major determinant of early left ventricular filling in animal experiments. However, suction remains incompletely characterized in the clinical setting. Methods and Results— First, we validated a method for measuring the spatio-temporal distributions of diastolic intraventricular pressure gradients and differences (DIVPDs) by digital processing color Doppler M-mode recordings. In 4 pigs, the error of peak DIVPD was 0.0±0.2 mm Hg (intraclass correlation coefficient, 0.95) compared with micromanometry. Forty patients with dilated cardiomyopathy (DCM) and 20 healthy volunteers were studied at baseline and during dobutamine infusion. A positive DIVPD (toward the apex) originated during isovolumic relaxation, reaching its peak shortly after mitral valve opening. Peak DIVPD was less than half in patients with DCM than in control subjects (1.2±0.6 versus 2.5±0.8 mm Hg, P<0.001). Dobutamine increased DIVPD in control subjects by 44% (P<0.001) but only by 23% in patients with DCM (P=NS). DIVPDs were the consequence of 2 opposite forces: a driving force caused by local acceleration, and a reversed (opposed to filling) convective force that lowered the total DIVPD by more than one third. In turn, local acceleration correlated with E-wave velocity and ejection fraction, whereas convective deceleration correlated with E-wave velocity and ventriculo:annular disproportion. Convective deceleration was highest among patients showing a restrictive filling pattern. Conclusions— Patients with DCM show an abnormally low diastolic suction and a blunted capacity to recruit suction with stress. By raising the ventriculo:annular disproportion, chamber remodeling proportionally increases convective deceleration and adversely affects left ventricular filling. These previously unreported mechanisms of diastolic dysfunction can be studied by using Doppler echocardiography.

Doppler-Derived Ejection Intraventricular Pressure Gradients Provide a Reliable Assessment of Left Ventricular Systolic Chamber Function

Background—Ejection intraventricular pressure gradients are caused by the systolic force developed by the left ventricle (LV). By postprocessing color Doppler M-mode (CDMM) images, we can measure noninvasively the ejection intraventricular pressure difference (EIVPD) between the LV apex and the outflow tract. This study was designed to assess the value of Doppler-derived EIVPDs as noninvasive indices of systolic chamber function. Methods and Results—CDMM images and pressure-volume (conductance) signals were simultaneously acquired in 9 minipigs undergoing pharmacological interventions and acute ischemia. Inertial, convective, and total EIVPD curves were calculated from CDMM recordings. Peak EIVPD closely correlated with indices of systolic function based on the pressure-volume relationship: peak elastance (within-animal R=0.98; between-animals R=0.99), preload recruitable stroke work (within-animal R=0.81; between-animals R=0.86), and peak of the first derivative of pressure corrected for end-diastolic volume (within-animal R=0.88; between-animals R=0.91). The correlation of peak inertial EIVPD with these indices was also high (all R>0.75). Load dependence of EIVPDs was studied in another 5 animals in which consecutive beats obtained during load manipulation were analyzed. During caval occlusion (40% EDV reduction), dP/dtmax, ejection fraction, and stroke volume significantly changed, whereas peak EIVPD remained constant. Aortic occlusion (40% peak LV pressure increase) significantly modified dP/dtmax, ejection fraction, and stroke volume; a nearly significant trend toward decreasing peak EIVPD was observed (P=0.06), whereas inertial EIVPD was unchanged (P=0.6). EIVPD beat-to-beat and interobserver variabilities were 2±12% and 5±11%, respectively. Conclusions—Doppler-derived EIVPDs provide quantitative, reproducible, and relatively load-independent indices of global systolic chamber function that correlate closely with currently available reference methods.

Noninvasive Assessment of the Right Ventricular Filling Pressure Gradient

Background— The physiological basis of right ventricular (RV) diastolic function remains incompletely studied in humans. The driving force responsible for RV filling, the pressure gradient along the RV inlet from the right atrium to the RV apex, has never been measured in the clinical setting. Methods and Results— We validated a method for measuring the RV filling pressure difference (RVFPD) from color Doppler M-mode recordings in 12 pigs undergoing interventions on RV preload, afterload, and lusitropic states (error, −0.1±0.4 mm Hg compared with micromanometers; intraclass correlation coefficient, 0.88). Peak early RVFPD correlated directly with mean right atrial pressure and inversely with the time constant of RV relaxation. In 21 patients with dilated cardiomyopathy, the peak RVFPD was 1.0 mm Hg (95% CI, 0.8 to 1.2), significantly lower than in age-matched control subjects (1.4 mm Hg; 95% CI, 1.2 to 1.6). In another population of 19 young healthy volunteers, the peak RVFPD was 2.3 mm Hg (95% CI, 2.0 to 2.6), which was reduced by nitroglycerine and esmolol and was augmented by volume overload and atropine infusions. RVFPD was generated almost exclusively by inertial forces. Conclusions— For the first time, the RV driving filling force can be accurately measured noninvasively in the clinical setting, and the method is sensitive to detect the effects of preload, chronotropic, and lusitropic states. In patients with dilated cardiomyopathy, the RV filling force is markedly reduced, indicating severely impaired RV relaxation. These findings suggest that this is a useful tool for improving the clinical assessment of RV diastolic function.

Noninvasive Estimation of the Rate of Relaxation by the Analysis of Intraventricular Pressure Gradients

Background—During late ejection, myocardial relaxation causes systolic flow to decelerate and stop, and this phenomenon is coupled with the generation of a pressure gradient inside the left ventricle (LV). We hypothesized that the peak reverse ejection intraventricular pressure difference (REIVPD) between the LV apex and the outflow tract could be a useful method to improve the assessment of LV relaxation using Doppler echocardiography. Methods and Results—Three sets of animal experiments and 1 clinical study were designed. In 6 pigs, a close relationship between REIVPD and the intensity of the relaxation wave (Rrm=0.89) was demonstrated using wave intensity analysis of high-fidelity pressure-volume-velocity data. In 19 animals, REIVPD sensitively detected modifications of the lusotropic state and closely correlated with the time constant of LV relaxation (&tgr;) within animals (Rrm=−0.93). Load-dependence analysis in 5 pigs showed that REIVPD remained stable up to values of 35% to 40% acute preload reduction. Clinical validation was tested in 50 patients (23 with normal systolic function) undergoing simultaneous Doppler echocardiography and high-fidelity LV pressure measurements on the same beat. REIVPD and tissue Doppler mitral annulus velocity (e′) were independently related to &tgr;, but the REIVPD · e′ product correlated better with &tgr; than either variable separately (bootstrap-corrected correlation coefficients: R=−0.84 versus −0.71, and −0.70, respectively, P<0.05). Area under the receiver operating characteristic curve to predict impaired relaxation (&tgr;>50 ms) for e′ · REIVPD was 0.96 (95% confidence interval, 0.85 to 0.99). Conclusions—The Doppler-derived REIVPD provides a sensitive, reliable, reproducible, and relatively load-independent index of the rate of LV relaxation. Combined with tissue Doppler measurements of longitudinal function, this method improves noninvasive assessment of LV relaxation in the clinical setting.

Diastolic chamber properties of the left ventricle assessed by global fitting of pressure-volume data: improving the gold standard of diastolic function

In cardiovascular research, relaxation and stiffness are calculated from pressure-volume (PV) curves by separately fitting the data during the isovolumic and end-diastolic phases (end-diastolic PV relationship), respectively. This method is limited because it assumes uncoupled active and passive properties during these phases, it penalizes statistical power, and it cannot account for elastic restoring forces. We aimed to improve this analysis by implementing a method based on global optimization of all PV diastolic data. In 1,000 Monte Carlo experiments, the optimization algorithm recovered entered parameters of diastolic properties below and above the equilibrium volume (intraclass correlation coefficients = 0.99). Inotropic modulation experiments in 26 pigs modified passive pressure generated by restoring forces due to changes in the operative and/or equilibrium volumes. Volume overload and coronary microembolization caused incomplete relaxation at end diastole (active pressure > 0.5 mmHg), rendering the end-diastolic PV relationship method ill-posed. In 28 patients undergoing PV cardiac catheterization, the new algorithm reduced the confidence intervals of stiffness parameters by one-fifth. The Jacobian matrix allowed visualizing the contribution of each property to instantaneous diastolic pressure on a per-patient basis. The algorithm allowed estimating stiffness from single-beat PV data (derivative of left ventricular pressure with respect to volume at end-diastolic volume intraclass correlation coefficient = 0.65, error = 0.07 ± 0.24 mmHg/ml). Thus, in clinical and preclinical research, global optimization algorithms provide the most complete, accurate, and reproducible assessment of global left ventricular diastolic chamber properties from PV data. Using global optimization, we were able to fully uncouple relaxation and passive PV curves for the first time in the intact heart.

The role of elastic restoring forces in right ventricular filling

AIMS The physiological determinants of RV diastolic function remain poorly understood. We aimed to quantify the contribution of elastic recoil to RV filling and determine its sensitivity to interventricular interaction. METHODS AND RESULTS High-fidelity pressure-volume loops and simultaneous 3-dimensional ultrasound sequences were obtained in 13 pigs undergoing inotropic modulation, volume overload, and acute pressure overload induced by endotoxin infusion. Using a validated method, we isolated elastic restoring forces from ongoing relaxation using conventional pressure-volume data. The RV contracted below the equilibrium volume in >75% of the data sets. Consequently, elastic recoil generated strong sub-atmospheric passive pressure at the onset of diastole [-3 (-4 to -2) mmHg at baseline]. Stronger restoring suction pressure was related to a shorter isovolumic relaxation period, a higher rapid filling fraction, and lower atrial pressures (all P < 0.05). Restoring forces were mostly determined by the position of operating volumes around the equilibrium volume. By this mechanism, the negative inotropic effect of beta-blockade reduced and sometimes abolished restoring forces. During acute pressure overload, restoring forces initially decreased, but recovered at advanced stages. This biphasic response was related to alterations of septal curvature induced by changes in the diastolic LV-RV pressure balance. The constant of elastic recoil was closely related to the constant of passive stiffness (R = 0.69). CONCLUSION The RV works as a suction pump, exploiting contraction energy to facilitate filling by means of strong elastic recoil. Restoring forces are influenced by the inotropic state and RV conformational changes mediated by direct ventricular interdependence.

Stochastic effects in a discrete RT model with critical behaviour

The effects of radiation on a tissue (being it healthy or cancerous) are well described by current linear-quadratic (LQ) radiobiological model for low absorbed doses around the 2 Gy often used in clinical fractionation. However, experimental data show a disagreement between the predicted and the observed effect of large doses. The Sotolongo et al. (2011) radiobiological (SRB) model, derived from Tsallis nonextensive entropy, has shown a good agreement with experiments for high absorbed doses, where LQ overestimates the dose required for a required effect. Other studies have reported a crossover in LQ model where its effects are underestimated for large doses. In this paper we develop a mechanistic version of the SRB model and show that it can reproduce both behaviors with a minimum set of assumptions. We compare the results of our simulations with some data reported in the literature. We also trivially adapt this model to fractionated radiotherapy and, in particular, to hypofractionation for which we draw some conclusions.

On feature extraction for noninvasive kernel estimation of left ventricular chamber function indices from echocardiographic images

This study was partially supported by research projects TEC2010-19263 (EX- CALIVUR) from Ministerio de Ciencia e Innovacion, TEC2013-48439-C4-1-R (PRINCIPIAS) from Ministerio de Economia y Competitividad, PRIN13_IYA12 from Universidad Rey Juan Carlos and grants IS09/02603, PS09/02602, and RD06/0010 (RECAVA), from the Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica (I+D+I), Instituto de Salud Carlos III?Ministerio de Economia y Competitividad, Spain, and Prometeo Project of the Secretariat for Higher Education, Science, Technology and Innovation of Ecuador. Author R. Santiago-Mozos is supported by the Juan de la Cierva Program (Ref: JCI-2011-11150) of the Ministerio de Ciencia e Innovacion, Spain.