Cardiac resynchronization: insight from experimental and computational models.

Cardiac resynchronization therapy (CRT) is a promising therapy for heart failure patients with a conduction disturbance, such as left bundle branch block. The aim of CRT is to resynchronize contraction between and within ventricles. However, about 30% of patients do not respond to this therapy. Therefore, a better understanding is needed for the relation between electrical and mechanical activation. In this paper, we focus on to what extent animal experiments and mathematical models can help in order to understand the pathophysiology of asynchrony to further improve CRT.

Esmolol and percutaneous cardiopulmonary bypass enhance myocardial salvage during ischemia in a dog model.

Despite recent advances in techniques of reperfusion for acute myocardial ischemia, myocardial salvage remains suboptimal. Beta-blockers have been shown to limit infarct size during acute ischemia, but their negative inotropic properties have limited their use. Cardiopulmonary bypass is an attractive technique for cardiac resuscitation because it can stabilize a hemodynamically compromised patient and potentially reduce myocardial oxygen consumption. In an attempt to maximize myocardial salvage in the setting of acute ischemia, the combination of esmolol, an ultrashort-acting beta-blocker, with percutaneous cardiopulmonary bypass was evaluated. Four groups of instrumented dogs underwent 2 hours of myocardial ischemia induced by occlusion of the proximal left anterior descending coronary artery, followed by 1 hour of reperfusion. Throughout the period of ischemia and reperfusion, esmolol plus percutaneous cardiopulmonary bypass was compared with esmolol alone, percutaneous cardiopulmonary bypass alone, and control conditions. After the reperfusion period, the extent of infarction of the left ventricle at risk was determined. Four animals had intractable arrhythmias: one in the esmolol plus bypass group, one in the esmolol group, and two in the control group. The extent of infarction of the left ventricle at risk was significantly reduced in the esmolol plus bypass group (30%) compared with bypass alone (52%), with esmolol alone (54%), and with the control groups (59%; p < 0.05). We conclude that in this experimental model the combination of esmolol with bypass improves myocardial salvage after ischemia and reperfusion.

Multi-scale modeling of excitation-contraction coupling in the normal and failing heart.

Here we describe new computational models of cardiac electromechanics starting from the cellular scale and building to the tissue, organ and system scales. We summarize application to human genetic diseases (LQT1 and LQT3) and to modeling of congestive heart failure.

Mechanical determinants of coronary blood flow during dynamic alterations in myocardial contractility.

Recently it has been proposed that the decrease in coronary blood flow (CBF) resulting from cardiac contraction referred to as systolic flow impediment (SFI) is dependent on the level of left ventricular elastance (Ees). The average rate of LV relaxation (Ravg) has been shown to be major determinant of diastolic flow development (DFD). We tested these hypotheses using the unique hemodynamic condition of pulsus alternans (PA) where end-systolic LV pressure and instantaneous Ees vary on beat-to-beat basis. In six mongrel dogs instrumented with LV and aortic manometers, ultrasonic dimension crystals, and Doppler coronary flow probes we measured phasic CBF and Ees during PA and control conditions. Maximal pressure development over time (dP/dtmax) and SFI were significantly different between weak (WB) and strong beats (SB) as were Ravg and DFD. Minimum CBF (Qmin) was not different between SB and WB; however, Qmin and peak Ees occurred nearly simultaneously in the WB. Qmin occurred much earlier than peak Ees in the strong and control beats. Plots of instantaneous LV elastance and CBF showed that for control beats and for the strong beats of PA CBF was similar during systole and diastole, suggesting elastance is a unique determinant of CBF. This was quantified as CBF at the time in either systole or diastole when elastance was half-maximal for that beat (E50). During the WB of PA, however, CBF at E50 was significantly higher during systole than during diastole. We conclude that while SFI and DFD are highly dependent on the dP/dt and Ravg, Ees is not a unique determinant of CBF under all conditions.

Evaluation of hypercholesterol diet-induced changes in viscoelastic properties of carotid circulation in pigs.

Measurements of pulsatile pressure and flow at the input of the left and right carotid arteries and a new lumped parameter model were used to quantify changes in the overall dynamic mechanical properties of the carotid circulation between five control diet-fed pigs and five pigs fed a hyperlipidemic diet for 16 wk. The model represents the portion of the circulation supplied by either the left or the right carotid artery and is characterized by five parameters: peripheral resistance (Rp), an overall inertance (L), and an overall frequency-dependent compliance constituted by a capacitor C (static compliance) in series with a Maxwell section, i.e., a capacitor Cd, in parallel with a resistor Rd. Rp was calculated as the ratio between mean pressure (P) and mean flow (Q). The other four parameters were estimated by fitting measured to model predicted flows. The average static compliance was reduced by 40% (P = 0.01) between normal (P = 62.0 +/- 4.3 mmHg) and hyperlipidemic diet-fed pigs (P = 62.7 +/- 4.7 mmHg). A significant reduction in the overall cross-sectional area was inferred from a 53% increase (P = 0.05) in L, whereas resistance vessel tone was unchanged as judged from estimates of Rp. No signs of occlusive disease were found in any of the animals.