Kinematic Modeling of the Determinants of Diastolic Function

Multiple modalities are routinely used in clinical cardiology to determine cardiovascular function, and many of the indexes derived from these modalities are causally interconnected. A correlative approach to cardiovascular function however, where indexes are correlated to disease presence and progression, fails to fully capitalize on the information content of the indexes. Causal quantitative modeling of cardiovascular physiology on the other hand offers a predictive rather than accommodative approach to cardiovascular function determination. In this work we apply a kinematic modeling approach to understanding diastolic function. We discuss novel insights related to the physiological determinants of diastolic function, and define novel causal indexes of diastolic function that go beyond the limitations of current established clinical indexes. Diastolic function is typically characterized by physiologists and cardiologists as being determined by the interplay between chamber stiffness, chamber relaxation/viscoelasticity, and chamber filling volume or load. In this work we provide kinematic modeling based analysis of each of these clinical diastolic function determinants. Considering the kinematic elastic (stiffness) components of filling, we argue for the universality of diastolic suction and define a novel in-vivo equilibrium volume. Application of this novel equilibrium volume in the clinical setting results in a novel approach to determination of global chamber stiffness. Considering the viscoelastic components of filling, we demonstrate the limitations associated with ignoring viscoelastic effects, an assumption often made in the clinical setting. We extend the viscoelastic component of filling into the invasive hemodynamic domain, and demonstrate the causal link between invasively recorded LV pressure and noninvasively recorded transmitral flow by describing a method for extracting flow contours from pressure signals alone. Finally, in considering load, we solve the problem of load dependence in diastolic function analysis. Indeed all traditional clinical indexes of diastolic function are load dependent, and therefore are imperfect indexes of intrinsic diastolic function. Applying kinematic modeling, we derive a load independent index of diastolic function. Validation involves showing that the index is indeed load-independent and can differentiate between control and diastolic dysfunction states. We apply this novel analysis to derive surrogates for filling pressure, and generalize the kinematic modeling approach to the analysis of isovolumic relaxation. To aid widespread adoption of the load independent index, we derive and validate simplified expressions for model-based physiological parameters of diastolic function. Our goal is to provide a causal approach to cardiovascular function analysis based on how things move, to explain prior phenomenological observations of others under a single causal paradigm, to discover `new physiology\u27, facilitate the discovery of more robust indexes of cardiovascular function, and provide a means for widespread adoption of the kinematic modeling approach suitable for the general clinical setting

Label-free high-throughput photoacoustic tomography of suspected circulating melanoma tumor cells in patients in vivo

Significance: Detection and characterization of circulating tumor cells (CTCs), a key determinant of metastasis, are critical for determining risk of disease progression, understanding metastatic pathways, and facilitating early clinical intervention. Aim: We aim to demonstrate label-free imaging of suspected melanoma CTCs. Approach: We use a linear-array-based photoacoustic tomography system (LA-PAT) to detect melanoma CTCs, quantify their contrast-to-noise ratios (CNRs), and measure their flow velocities in most of the superficial veins in humans. Results: With LA-PAT, we successfully imaged suspected melanoma CTCs in patients in vivo, with a CNR >9. CTCs were detected in 3 of 16 patients with stage III or IV melanoma. Among the three CTC-positive patients, two had disease progression; among the 13 CTC-negative patients, 4 showed disease progression. Conclusions: We suggest that LA-PAT can detect suspected melanoma CTCs in patients in vivo and has potential clinical applications for disease monitoring in melanoma

Stiffness and relaxation components of the exponential and logistic time constants may be used to derive a load-independent index of isovolumic pressure decay

In current practice, empirical parameters such as the monoexponential time constant τ or the logistic model time constant τL are used to quantitate isovolumic relaxation. Previous work indicates that τ and τL are load dependent. A load-independent index of isovolumic pressure decline (LIIIVPD) does not exist. In this study, we derive and validate a LIIIVPD. Recently, we have derived and validated a kinematic model of isovolumic pressure decay (IVPD), where IVPD is accurately predicted by the solution to an equation of motion parameterized by stiffness (Ek), relaxation (τc), and pressure asymptote (P∞) parameters. In this study, we use this kinematic model to predict, derive, and validate the load-independent index MLIIIVPD. We predict that the plot of lumped recoil effects [Ek·(P*max − P∞)] versus resistance effects [τc·(dP/dtmin)], defined by a set of load-varying IVPD contours, where P*max is maximum pressure and dP/dtmin is the minimum first derivative of pressure, yields a linear relation with a constant (i.e., load independent) slope MLIIIVPD. To validate the load independence, we analyzed an average of 107 IVPD contours in 25 subjects (2,669 beats total) undergoing diagnostic catheterization. For the group as a whole, we found the Ek·(P*max − P∞) versus τc·(dP/dtmin) relation to be highly linear, with the average slope MLIIIVPD = 1.107 ± 0.044 and the average r2 = 0.993 ± 0.006. For all subjects, MLIIIVPD was found to be linearly correlated to the subject averaged τ (r2 = 0.65), τL(r2 = 0.50), and dP/dtmin (r2 = 0.63), as well as to ejection fraction (r2 = 0.52). We conclude that MLIIIVPD is a LIIIVPD because it is load independent and correlates with conventional IVPD parameters. Further validation of MLIIIVPD in selected pathophysiological settings is warranted