Asynchronous left ventricular (LV) contraction is the most common cardiac abnormality and, if severe, impairs LV pump function, induces cardiac dilation and heart failure remodeling. Ventricular pacing usually increases contraction asynchrony and induces cardiac dilation even when contractility is normal. We hypothesize that LV contraction asynchrony reduces LV ejection efficiency, defined by the ratio of LV stroke work to myocardial O2 consumption (MVO2), by causing LV dilation without altering intrinsic contractility. We define LV ejection effectiveness as the synchrony of contraction of all contractile elements. Importantly, recent clinical trials of cardiac resynchronization therapy (CRT) in patients with dilated cardiomyopathy and prolonged QRS have shown that gated bi-ventricular pacing improves LV ejection pressure, decreases cardiac volumes and induces reverse remodeling in some but not all subjects. We hypothesize that all the beneficial effects of CRT come from its ability to improve LV contraction synchrony. We believe that these clinically opposite effects of pacing are explained by opposite changes in contraction synchrony. The relation between MVO2, LV ejection asynchrony and ejection effectiveness is unknown. We will develop a novel application of the assessment of LV ejection efficiency combining regional phase angle analysis with Fourier analysis of both phase angle and amplitude dispersion from echocardiographic data. We propose to quantify this asynchrony at the bedside in both animal and human models using tissue Doppler imaging (TDI). We have recently developed and validated a quantitative model to assess LV ejection effectiveness using regional phase angle analysis. However, this technique requires invasive monitoring and are not suitable for general clinical use. Importantly, we have also developed and validated quantitative methods of analyzing transthoracic echocardiographic LV images using TDI and acoustic quantification (AQ) algorithms. These powerful non-invasive tools allow us to define regional myocardial movement. Presently, there is no established method of analyzing these data to objectively quantify contraction asynchrony. We propose to couple our asynchrony analysis with our quantitative AQ and TDI techniques to create a clinically relevant tool to assess LV ejection effectiveness. We will use our established isolated perfused rabbit heart (Langendorf preparation) model to validate the relation between MVO2 and asynchronous LV contraction. We will use our intact anesthetized canine model under conditions of varying contraction asynchrony induced by selective pacing, mock CRT and regional ischemia and reperfusion to create an on-line TDI analysis algorithm. Finally, we shall study human subjects before and after CRT and non-CRT subjects to ascertain if we can predict which subjects will benefit from CRT and where in the ventricle CRT pacing would be optimal. Potentially, CRT could be used in subjects before they develop heart failure remodeling. We will test two related hypotheses. First, that increased global LV asynchrony induces parallel shifts in LV volume for a constant ejection pressure such that MVO2 increases as a function of the parallel shift of the LV end-systolic pressure-volume relation. Second, that LV ejection effectiveness, measured by AQ and TDI in both clinically relevant canine models of LV contraction asynchrony and humans with cardiac disease, can be quantified as both the sum of the amplitude-corrected phase angle dispersion among LV regions and as the cross correlation of amplitude-corrected phase angles. The ultimate goal of this proposal is to develop and validate an echocardiographic-based algorithm that quantifies LV ejection effectiveness by merging both power and synchrony of contraction into a common metric.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073198-02
Application #
6937215
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Buxton, Denis B
Project Start
2004-08-15
Project End
2008-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
2
Fiscal Year
2005
Total Cost
$477,240
Indirect Cost
Name
University of Pittsburgh
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Pinsky, Michael R; Kim, Hyung Kook; Zenker, Sven et al. (2016) Differential Effects of Left Ventricular Pacing Sites on Regional Contraction Patterns and Global Performance. J Cardiothorac Vasc Anesth 30:709-15
Pinsky, Michael R (2015) Understanding preload reserve using functional hemodynamic monitoring. Intensive Care Med 41:1480-2
Pinsky, Michael R (2015) Defining the boundaries of preload responsiveness at the bedside. Pediatr Crit Care Med 16:82-3
Pinsky, Michael R (2015) Functional hemodynamic monitoring. Crit Care Clin 31:89-111
Pinsky, Michael R (2014) My paper 20 years later: Effect of positive end-expiratory pressure on right ventricular function in humans. Intensive Care Med 40:935-41
Zenker, Sven; Kim, Hyung Kook; Clermont, Gilles et al. (2013) Robust model-based quantification of global ventricular torsion from spatially sparse three-dimensional time series data by orthogonal distance regression: evaluation in a canine animal model under different pacing regimes. Pacing Clin Electrophysiol 36:13-23
García, Xaime; Simon, Peter; Guyette, Francis X et al. (2013) Noninvasive assessment of acute dyspnea in the ED. Chest 144:610-615
Cove, Matthew E; Pinsky, Michael R (2012) Carboxyhemoglobin levels in medical intensive care patients. Crit Care 16:411; author reply 411
Johnson, Lauren; Lamia, Bouchra; Kim, Hyung Kook et al. (2012) Physiological relevance of quantifying segmental contraction synchrony. Pacing Clin Electrophysiol 35:174-87
Lamia, Bouchra; Tanabe, Masaki; Tanaka, Hidekazu et al. (2011) Left ventricular systolic torsion correlates global cardiac performance during dyssynchrony and cardiac resynchronization therapy. Am J Physiol Heart Circ Physiol 300:H853-8

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