A pharmacologic activator of endothelial KCa channels increases systemic conductance and reduces arterial pressure in an anesthetized pig model.

SKA-31, an activator of endothelial KCa2.3 and KCa3.1 channels, reduces systemic blood pressure in mice and dogs, however, its effects in larger mammals are not well known. We therefore examined the hemodynamic effects of SKA-31, along with sodium nitroprusside (SNP), in anesthetized, juvenile male domestic pigs. Experimentally, continuous measurements of left ventricular (LV), aortic and inferior vena cava (IVC) pressures, along with flows in the ascending aorta, carotid artery, left anterior descending coronary artery and renal artery, were performed during acute administration of SKA-31 (0.1, 0.3, 1.0, 3.0 and 5.0mg/ml/kg) and a single dose of SNP (5.0 µg/ml/kg). SKA-31 dose-dependently reduced mean aortic pressure (mPAO), with the highest dose decreasing mPAO to a similar extent as SNP (-23 ± 3 and -28 ± 4 mmHg, respectively). IVC pressure did not change. Systemic conductance and conductance in coronary and carotid arteries increased in response to SKA-31 and SNP, but renal artery conductance was unaffected. There was no change in either LV stroke volume (SV) or heart rate (versus the preceding control) for any infusion. With no change in SV, drug-evoked decreases in LV stroke work (SW) were attributed to reductions in mPAO (SW vs. mPAO, r(2)=0.82, P<0.001). In summary, SKA-31 dose-dependently reduced mPAO by increasing systemic and arterial conductances. Primary reductions in mPAO by SKA-31 largely account for associated decreases in SW, implying that SKA-31 does not directly impair cardiac contractility.

Defining left ventricular apex-to-base twist mechanics computed from high-resolution 3D echocardiography: validation against sonomicrometry.

OBJECTIVES: To compute left ventricular (LV) twist from 3-dimensional (3D) echocardiography. BACKGROUND: LV twist is a sensitive index of cardiac performance. Conventional 2-dimensional based methods of computing LV twist are cumbersome and subject to errors. METHODS: We studied 10 adult open-chest pigs. The pre-load to the heart was altered by temporary controlled occlusion of the inferior vena cava, and myocardial ischemia was produced by ligating the left anterior descending coronary artery. Full-volume 3D loops were reconstructed by stitching of pyramidal volumes acquired from 7 consecutive heart beats with electrocardiography gating on a Philips IE33 system (Philips Medical Systems, Andover, Massachusetts) at baseline and other steady states. Polar coordinate data of the 3D images were entered into an envelope detection program implemented in MatLab (The MathWorks, Inc., Natick, Massachusetts), and speckle motion was tracked using nonrigid image registration with spline-based transformation parameterization. The 3D displacement field was obtained, and rotation at apical and basal planes was computed. LV twist was derived as the net difference of apical and basal rotation. Sonomicrometry data of cardiac motion were also acquired from crystals anchored to epicardium in apical and basal planes at all states. RESULTS: The 3D dense tracking slightly overestimated the LV twist, but detected changes in LV twist at different states and showed good correlation (r = 0.89) when compared with sonomicrometry-derived twist at all steady states. In open chest pigs, peak cardiac twist was increased with reduction of pre-load from inferior vena cava occlusion from 6.25 degrees +/- 1.65 degrees to 9.45 degrees +/- 1.95 degrees . With myocardial ischemia from left anterior descending coronary artery ligation, twist was decreased to 4.90 degrees +/- 0.85 degrees (r = 0.8759). CONCLUSIONS: Despite lower spatiotemporal resolution of 3D echocardiography, LV twist and torsion can be computed accurately.

A 2D FE model of the heart demonstrates the role of the pericardium in ventricular deformation.

During pulmonary artery constriction (PAC), an experimental model of acute right ventricular (RV) pressure overload, the interventricular septum flattens and inverts. Finite element (FE) analysis has shown that the septum is subject to axial compression and bending when so deformed. This study examines the effects of acute PAC on the left ventricular (LV) free wall and the role the pericardium may play in these effects. In eight open-chest anesthetized dogs, LV, RV, aortic, and pericardial pressures were recorded under control conditions and with PAC. Model dimensions were derived from two-dimensional echocardiography minor-axis images of the heart. At control (pericardium closed), FE analysis showed that the septum was concave to the LV; stresses in the LV, RV, and septum were low; and the pericardium was subject to circumferential tension. With PAC, RV end-diastolic pressure exceeded LV pressure and the septum inverted. Compressive stresses developed circumferentially in the septum out to the RV insertion points, forming an arch-like pattern. Sharp bending occurred near the insertion points, accompanied by flattening of the LV free wall. With the pericardium open, the deformations and stresses were different. The RV became much larger, especially with PAC. With PAC, the arch-like circumferential stresses still developed in the septum, but their magnitudes were reduced, compared with the pericardium-closed case. There was no free wall inversion and flattening was less. From these FE results, the pericardium has a significant influence on the structural behavior of the septum and the LV and RV free walls. Furthermore, the deformation of the heart is dependent on whether the pericardium is open or closed.

Compression induced by RV pressure overload decreases regional coronary blood flow in anesthetized dogs.

Pulmonary artery constriction (PAC), a model of right ventricular (RV) pressure overload, flattens or inverts the septum and may flatten the left ventricular (LV) free wall. Finite element (FE) analysis predicts that such deformations may cause substantial compression. This study tests the hypothesis that deformation-induced myocardial compressive stress impedes coronary blood flow (CBF). Colored microspheres ( approximately 2 x 10(6)) were injected into the left atrium of 13 open-chest, anesthetized dogs under control conditions and during PAC, which decreased the end-diastolic transseptal pressure gradient (LV - RV) from 1.6 +/- 1.3 to -3.4 +/- 1.7 mmHg. Septal and LV deformation was assessed with the use of two-dimensional echocardiography, and by FE analysis, the hydrostatic component of stress was assessed. Postmortem, a 2.5-cm wide, LV equatorial ring was divided into 16 endocardial and epicardial samples. PAC decreased CBF in the FE-predicted compression zones, areas with the greatest compression having the greatest reductions in CBF. During PAC, compression reached a maximum of 25.3 +/- 1.8 mmHg on the (LV) endocardial sides of the RV insertion points, areas that saw CBF decrease from 1.05 +/- 0.08 to 0.68 +/- 0.05 ml.min(-1).g(-1) (P < 0.001), more than 30%. CBF decreased (from 1.08 +/- 0.07 to 0.81 +/- 0.07 ml.min(-1).g(-1); P < 0.001) on the RV side of the midseptum, an area with as much as 16.0 +/- 1.0 mmHg of compression. Overall, average compressions of 10 mmHg decreased CBF by approximately 30%. We conclude that acute RV pressure overload deforms the septum and LV and induces compressive stresses that reduce CBF substantially. This may help explain why some patients with pulmonary hypertension and no critical coronary disease have chest discomfort indistinguishable from angina pectoris.