Transmural sheet strains in the lateral wall of the ovine left ventricle

In an attempt to provide a better understanding of our finding that regions with contracting left ventricular myofibers need not develop a significant transmural systolic wall thickening gradient, the analytic approach of Costa et al. was applied to the four-dimensional dynamic data obtained 1 and 8 wk after surgical implantation of transmural radiopaque beads in the lateral equatorial left ventricular wall in seven ovine hearts. Quantitative histology of tissue blocks demonstrated that fiber angles varied linearly across the wall in this region from -37 degrees in the subepicardium to +18 degrees in the subendocardium. Sheet angles exhibited a pleated-sheet behavior, alternating sign from subepicardium to subendocardium. From end diastole (reference configuration) to end systole (deformed configuration), fiber strain was uniformly negative, sheet extension and sheet thickening were uniformly positive, and sheet-normal shear contributed to wall thickening at all wall depths. Subepicardial radial wall thickening increased significantly from week 1 to week 8, with significant increases in the contributions from subepicardial sheet extension and sheet-normal shear. At 1 and 8 wk, the contribution of sheet-normal shear to wall thickening was substantial at all transmural depths; the contribution of sheet extension to wall thickening was greatest in the subepicardium and least in the subendocardium, and the contribution of sheet thickening to wall thickening was greatest in the subendocardium and least in the subepicardium. A mechanistic model is proposed that provides a working hypothesis that a selective decrease in subepicardial intercellular matrix stiffness is responsible for elimination of the transmural wall thickening gradient 1-8 wk after marker implantation surgery.     

Regional nonuniformity of normal adult human left ventricle

Regional nonuniformity is a feature of both diseased and normal left ventricles (LV). With the use of magnetic resonance (MR) myocardial tagging, we performed three-dimensional strain analysis on 87 healthy adults in local cardiac and fiber coordinate systems (radial, circumferential, longitudinal, and fiber strains) to characterize normal nonuniformities and to test the validity of wall thickening as a parameter of regional function. Regional morphology included wall thickness and radii of curvature measurements. With respect to transmural nonuniformity, subendocardial strains exceeded subepicardial strains. Going from base to apex, wall thickness and circumferential radii of curvature decreased, whereas longitudinal radii of curvature increased. All of the strains increased from LV base to apex, resulting in a higher ejection fraction (EF) at the apex than at the base (70.9 +/- 0.4 vs. 62.4 +/- 0.4%; means +/- SE, P < 0.0001). When we looked around the circumference of the ventricle, the anterior part of the LV was the flattest and thinnest and showed the largest wall thickening (46.6 +/- 1.2%) but the lowest EF (64.7 +/- 0.5%). The posterior LV wall was thicker, more curved, and showed a lower wall thickening (32.8 +/- 1.0%) but a higher EF (71.3 +/- 0.5%). The regional contribution of the LV wall to the ejection of blood is thus highly variable and is not fully characterized by wall thickening alone. Differences in regional LV architecture and probably local stress are possible explanations for this marked functional nonuniformity.     

Transmural distribution of metabolic abnormalities and glycolytic activity during dobutamine-induced demand ischemia

The heterogeneity across the left ventricular wall is characterized by higher rates of oxygen consumption, systolic thickening fraction, myocardial perfusion, and lower energetic state in the subendocardial layers (ENDO). During dobutamine stimulation-induced demand ischemia, the transmural distribution of energy demand and metabolic markers of ischemia are not known. In this study, hemodynamics, transmural high-energy phosphate (HEP), 2-deoxyglucose-6-phosphate (2-DGP) levels, and myocardial blood flow (MBF) were determined under basal conditions, during dobutamine infusion (DOB: 20 microg x kg(-1) x min(-1) iv), and during coronary stenosis + DOB + 2-deoxyglucose (2-DG) infusion. DOB increased rate pressure products (RPP) and MBF significantly without affecting the subendocardial-to-subepicardial blood flow ratio (ENDO/EPI) or HEP levels. During coronary stenosis + DOB + 2-DG infusion, RPP, ischemic zone (IZ) MBF, and ENDO/EPI decreased significantly. The IZ ratio of creatine phosphate-to-ATP decreased significantly [2.30 +/- 0.14, 2.06 +/- 0.13, and 2.04 +/- 0.11 to 1.77 +/- 0.12, 1.70 +/- 0.11, and 1.72 +/- 0.12 for EPI, midmyocardial (MID), and ENDO, respectively], and 2-DGP accumulated in all layers, as evidenced by the 2-DGP/PCr (0.55 +/- 0.12, 0.52 +/- 0.10, and 0.37 +/- 0.08 for EPI, MID, and ENDO, respectively; P < 0.05, EPI > ENDO). In the IZ the wet weight-to-dry weight ratio was significantly increased compared with the normal zone (5.9 +/- 0.5 vs. 4.4 +/- 0.4; P < 0.05). Thus, in the stenotic perfused bed, during dobutamine-induced high cardiac work state, despite higher blood flow, the subepicardial layers showed the greater metabolic changes characterized by a shift toward higher carbohydrate metabolism, suggesting that a homeostatic response to high-cardiac work state is characterized by more glucose utilization in energy metabolism.     

压力负荷性心衰小鼠左心室跨壁L-型钙电流的变化

为了观察正常和心衰时心内膜下和心外膜下心肌细胞L-型钙电流(ICa-L)的差别,我们采用主动脉弓狭窄的方法建立小鼠压力超负荷性心衰模型,采用全细胞膜片钳技术记录了正常、主动脉狭窄(band)及假手术对照(sham)组动物左心室游离壁内、外膜下心肌细胞的动作电位时程(action potential duration,APD)和ICa-L。结果显示:(1)与sham组同龄的正常小鼠左心室心内膜下细胞动作电位复极达90％的时程(APD90)为(38．2±6．44)ms,较心外膜下细胞的APD90(15.67±5.31)ms明显延长,二者的比值约为2．5:1;内膜下细胞和外膜下细胞ICa-L密度没有差异,峰电流密度分别为(-2.7±0.49)pA/pF和(-2.54±0．53)pA/pF;(2)Band组内、外膜下细胞的动作电位复极达50％的时程(APD50)、APD90均较sham组显著延长,尤以内膜下细胞延长突出,分别较sham组延长了400％和360％,内、外膜下细胞APD90的比值约为4.2:1;(3)与sham组相比, band组内膜下细胞ICa-L密度显著减小,在+10 mV～+40 mV的4个电压下分别降低了20．2％、21．4％、21.6％和25.7％(P< 0．01),但其激活电位、峰电位和翻转电位没有改变;band组外膜下细胞的ICa-L密度与同期sham组相比无明显变化;band组钙通道激活、失活及复活的动力学特征与sham组相比没有改变。以上结果提示,生理状态下小鼠左心室内、外膜下细胞ICa-L密度不存在明显差别,提示ICa-L与APD跨壁异质性的产生无关;心衰时左心室内、外膜下细胞APD明显延长,以内膜下细胞延长尤为突出,内膜下细胞ICa-L密度明显减少,而外膜下细胞ICa-L密度无明显改变,这种ICa-L的非同步变化在心衰时可能起到对抗APD延长、减少复极离散度的有益作用。     

Dynamics of flow velocities in endocardial and epicardial coronary arterioles

The subendocardium is the most vulnerable area of the left ventricle to the effects of hypoperfusion and ischemia. Despite this well-acknowledged observation, the mechanisms underlying this susceptibility are not elucidated, although numerous explanations including differences in transmural distribution of hemodynamics, metabolism, and wall stresses have been proposed. Our goal was to make dynamic measurements of endocardial and epicardial flow velocities, which reflect hemodynamic and wall stresses, to approach this problem. We measured blood flow velocities in subendocardial and subepicardial coronary arterioles of in vivo beating canine hearts using a high-speed, charge-coupled device, intravital videomicroscope with a rod-probe lens. Subendocardial flow was characterized by remarkable systolic flow-velocity reversal (systolic slosh ratio, 84%; measurable velocity of retrograde flow, faster than -40 mm/s), which contrasted to predominant forward-flow velocity during systole in the subepicardial arterioles (systolic slosh ratio, 25%; maximum velocity, approximately -20 mm/s; P < 0.0005 and 0.05 vs. subendocardial arterioles, respectively). We speculate that this retrograde flow is "wasteful," because this volume must be refilled during the subsequent diastole, which thereby detracts from the net perfusion as well as the time for perfusion. Accordingly, we also believe that the retrograde systolic blood flow contributes to the vulnerability of the subendocardium to ischemia.     

The impact of endurance exercise training on left ventricular systolic mechanics

Although exercise training-induced changes in left ventricular (LV) structure are well characterized, adaptive functional changes are incompletely understood. Detailed echocardiographic assessment of LV systolic function was performed on 20 competitive rowers (10 males and 10 females) before and after endurance exercise training (EET; 90 days, 10.7 +/- 1.1 h/wk). Structural changes included LV dilation (end-diastolic volume = 128 +/- 25 vs. 144 +/- 28 ml, P < 0.001), right ventricular (RV) dilation (end-diastolic area = 2,850 +/- 550 vs. 3,260 +/- 530 mm2, P < 0.001), and LV hypertrophy (mass = 227 +/- 51 vs. 256 +/- 56 g, P < 0.001). Although LV ejection fraction was unchanged (62 +/- 3% vs. 60 +/- 3%, P = not significant), all direct measures of LV systolic function were altered. Peak systolic tissue velocities increased significantly (basal lateral S'Delta = 0.9 +/- 0.6 cm/s, P = 0.004; and basal septal S'Delta = 0.8 +/- 0.4 cm/s, P = 0.008). Radial strain increased similarly in all segments, whereas longitudinal strain increased with a base-to-apex gradient. In contrast, circumferential strain (CS) increased in the LV free wall but decreased in regions adjacent to the RV. Reductions in septal CS correlated strongly with changes in RV structure (DeltaRV end-diastolic area vs. DeltaLV septal CS; r2 = 0.898, P < 0.001) and function (Deltapeak RV systolic velocity vs. DeltaLV septal CS, r2 = 0.697, P < 0.001). EET leads to significant changes in LV systolic function with regional heterogeneity that may be secondary to concomitant RV adaptation. These changes are not detected by conventional measurements such as ejection fraction.     

Does coronary vasodilation after adenosine override endothelin-1-induced coronary vasoconstriction?

In vivo evaluation of the transmural extension of myocardial infarction (TEI) is crucial to prediction of viability and prognosis. With the rise of transgenic technology, murine myocardial infarction (MI) models are increasingly used. Our study aimed to evaluate systolic strain rate (SR), a new parameter of regional function, to quantify TEI in a murine model of acute MI induced by various durations of ischemia followed by 24 h of reperfusion. Global and regional left ventricular (LV) function were assessed by echocardiography (13 MHz, Vivid 7, GE) in 4 groups of wild-type mice (C57BL/6, 2 mo old): a sham-treated group (n = 10) and three MI groups [30 (n = 11), 60 (n = 10), and 90 (n = 9) min of left coronary artery occlusion]. Conventional LV dimensions, anterior wall (AW) thickening, and peak systolic SR were measured before and 24 h after reperfusion. Area at risk (AR) was measured by blue dye and infarct size (area of necrosis, AN) and TEI by triphenyltetrazolium chloride staining. AN increased with ischemia duration (25 +/- 2%, 56 +/- 5%, 71 +/- 6% of AR for 30, 60, and 90 min, respectively; P < 0.05). LV end-diastolic volume significantly increased with ischemia duration (30 +/- 5, 34 +/- 5, 43 +/- 5 microl; P < 0.05), whereas LV ejection fraction decreased (63 +/- 5%, 58 +/- 6%, 46 +/- 5%; P < 0.05). AW thickening decrease was not influenced by ischemia duration. Conversely, systolic SR decreased with ischemia duration (13 +/- 5, 4 +/- 3, -2 +/- 6 s(-1); P < 0.05) and was significantly correlated with TEI (r = 0.89, P < 0.01). Receiver operating characteristic (ROC) curves identified systolic SR as the most accurate parameter to predict TEI. In conclusion, in a murine model of MI, SR imaging is superior to conventional echocardiography to predict TEI early after MI.     

Mismatch between uniform increase in cardiac glucose uptake and regional contractile dysfunction in pacing-induced heart failure

Increased glucose utilization and regional differences in contractile function are well-known alterations of the failing heart and play an important pathophysiological role. We tested whether, similar to functional derangement, changes in glucose uptake develop following a regional pattern. Heart failure was induced in 13 chronically instrumented minipigs by pacing the left ventricular (LV) free wall at 180 beats/min for 3 wk. Regional changes in contractile function and stress were assessed by magnetic resonance imaging, whereas regional flow and glucose uptake were measured by positron emission tomography utilizing, respectively, the radiotracers [(13)N]ammonia and (18)F-deoxyglucose. In heart failure, LV end-diastolic pressure was 20 +/- 4 mmHg, and ejection fraction was 35 +/- 4% (all P < 0.05 vs. control). Sustained pacing-induced dyssynchronous LV activation caused a more pronounced decrease in LV systolic thickening (7.45 +/- 3.42 vs. 30.62 +/- 8.73%, P < 0.05) and circumferential shortening (-4.62 +/- 1.0 vs. -7.33 +/- 1.2%, P < 0.05) in the anterior/anterior-lateral region (pacing site) compared with the inferoseptal region (opposite site). Conversely, flow was reduced significantly by approximately 32% compared with control and was lower in the opposite site region. Despite these nonhomogeneous alterations, regional end-systolic wall stress was uniformly increased by 60% in the failing LV. Similar to wall stress, glucose uptake markedly increased vs. control (0.24 +/- 0.004 vs. 0.07 +/- 0.01 micromol x min(-1) x g(-1), P < 0.05), with no significant regional differences. In conclusion, high-frequency pacing of the LV free wall causes a dyssynchronous pattern of contraction that leads to progressive cardiac failure with a marked mismatch between increased glucose uptake and regional contractile dysfunction.     

Cardiac atrophy after bed rest and spaceflight.

Cardiac muscle adapts well to changes in loading conditions. For example, left ventricular (LV) hypertrophy may be induced physiologically (via exercise training) or pathologically (via hypertension or valvular heart disease). If hypertension is treated, LV hypertrophy regresses, suggesting a sensitivity to LV work. However, whether physical inactivity in nonathletic populations causes adaptive changes in LV mass or even frank atrophy is not clear. We exposed previously sedentary men to 6 (n = 5) and 12 (n = 3) wk of horizontal bed rest. LV and right ventricular (RV) mass and end-diastolic volume were measured using cine magnetic resonance imaging (MRI) at 2, 6, and 12 wk of bed rest; five healthy men were also studied before and after at least 6 wk of routine daily activities as controls. In addition, four astronauts were exposed to the complete elimination of hydrostatic gradients during a spaceflight of 10 days. During bed rest, LV mass decreased by 8.0 +/- 2.2% (P = 0.005) after 6 wk with an additional atrophy of 7.6 +/- 2.3% in the subjects who remained in bed for 12 wk; there was no change in LV mass for the control subjects (153.0 +/- 12.2 vs. 153.4 +/- 12.1 g, P = 0.81). Mean wall thickness decreased (4 +/- 2.5%, P = 0.01) after 6 wk of bed rest associated with the decrease in LV mass, suggesting a physiological remodeling with respect to altered load. LV end-diastolic volume decreased by 14 +/- 1.7% (P = 0.002) after 2 wk of bed rest and changed minimally thereafter. After 6 wk of bed rest, RV free wall mass decreased by 10 +/- 2.7% (P = 0.06) and RV end-diastolic volume by 16 +/- 7.9% (P = 0.06). After spaceflight, LV mass decreased by 12 +/- 6.9% (P = 0.07). In conclusion, cardiac atrophy occurs during prolonged (6 wk) horizontal bed rest and may also occur after short-term spaceflight. We suggest that cardiac atrophy is due to a physiological adaptation to reduced myocardial load and work in real or simulated microgravity and demonstrates the plasticity of cardiac muscle under different loading conditions.     

Changes in regional myocardial volume during the cardiac cycle: implications for transmural blood flow and cardiac structure

Although previous studies report a reduction in myocardial volume during systole, myocardial volume changes during the cardiac cycle have not been quantitatively analyzed with high spatiotemporal resolution. We studied the time course of myocardial volume in the anterior mid-left ventricular (LV) wall of normal canine heart in vivo (n = 14) during atrial or LV pacing using transmurally implanted markers and biplane cineradiography (8 ms/frame). During atrial pacing, there was a significant transmural gradient in maximum volume decrease (4.1, 6.8, and 10.3% at subepi, midwall, and subendo layer, respectively, P = 0.002). The rate of myocardial volume increase during diastole was 4.7 +/- 5.8, 6.8 +/- 6.1, and 10.8 +/- 7.7 ml.min(-1).g(-1), respectively, which is substantially larger than the average myocardial blood flow in the literature measured by the microsphere method (0.7-1.3 ml.min(-1).g(-1)). In the early activated region during LV pacing, myocardial volume began to decrease before the LV pressure upstroke. We conclude that the volume change is greater than would be estimated from the known average transmural blood flow. This implies the existence of blood-filled spaces within the myocardium, which could communicate with the ventricular lumen. Our data in the early activated region also suggest that myocardial volume change is caused not by the intramyocardial tissue pressure but by direct impingement of the contracting myocytes on the microvasculature.     

Evaluation of transmural distribution of viable muscle by myocardial strain profile and dobutamine stress echocardiography

Transmural distribution of viable myocardium in the ischemic myocardium has not been quantified and fully elucidated. To address this issue, we evaluated transmural myocardial strain profile (TMSP) in dogs with myocardial infarction using a newly developed tissue strain imaging. TMSP was obtained from the posterior wall at the epicardial left ventricular short-axis view in 13 anesthetized open-chest dogs. After control measurements, the left circumflex coronary artery was occluded for 90 min to induce subendocardial infarction (SMI). Subsequently, latex microbeads (90 microm) were injected in the same artery to create transmural infarction (TMI). In each stage, measurements were done before and after dobutamine challenge (10 microg.kg(-1).min(-1) for 10 min) to estimate transmural myocardial viability. Strain in the subendocardium in the control stage increased by dobutamine (from 53.6 +/- 17.1 to 73.3 +/- 21.8%, P < 0.001), whereas that in SMI and TMI stages was almost zero at baseline and did not increase significantly by dobutamine [from 0.8 +/- 8.8 to 1.3 +/- 7.0%, P = not significant (NS) for SMI, from -3.9 +/- 5.6 to -1.9 +/- 6.0%, P = NS for TMI]. Strain in the subepicardium increased by dobutamine in the control stage (from 23.9 +/- 6.1 to 26.3 +/- 6.4%, P < 0.05) and in the SMI stage (from 12.4 +/- 7.3 to 27.1 +/- 8.8%, P < 0.005), whereas that in the TMI stage did not change (from -1.0 +/- 7.8 to -0.7 +/- 8.3%, P = NS). In SMI, the subendocardial contraction was lost, but the subepicardium showed a significant increase in contraction with dobutamine. However, in TMI, even the subepicardial increase was not seen. Assessment of transmural strain profile using tissue strain imaging was a new and useful method to estimate transmural distribution of the viable myocardium in myocardial infarction.     

Effects of coronary sinus pressure elevation on coronary blood flow distribution in dogs with normal preload

Coronary sinus pressure (Pcs) elevation shifts the diastolic coronary pressure-flow relation (PFR) of the entire left ventricular myocardium to a higher pressure intercept. This finding suggests that Pcs is one determinant of zero-flow pressure (Pzf) and challenges the existence of a vascular waterfall mechanism in the coronary circulation. To determine whether coronary sinus or tissue pressure is the effective coronary back pressure in different layers of the left ventricular myocardium, the effect of increasing Pcs was studied while left ventricular preload was low. PFRs were determined experimentally by graded constriction of the circumflex coronary artery while measuring flow using a flowmeter. Transmural myocardial blood flow distribution was studied (15-micron radioactive spheres) at steady state, during maximal coronary artery vasodilatation at three points on the linear portion of the circumflex PFR both at low and high diastolic Pcs (7 +/- 3 vs. 22 +/- 5 mmHg; p less than 0.0001) (1 mmHg = 133.322 Pa). In the uninstrumented anterior wall the blood flow measurements were obtained in triplicate at the two Pcs levels. From low to high Pcs, mean aortic (98 +/- 23 mmHg) and left atrial (5 +/- 3 mmHg) pressure, percent diastolic time (49 +/- 7%), percent left ventricular wall thickening (32 +/- 4%), and percent myocardial lactate extraction (15 +/- 12%) were not significantly changed. Increasing Pcs did not alter the slope of the PFR; however, the Pzf increased in the subepicardial layer (p less than 0.0001), whereas in the subendocardial layer Pzf did not change significantly. Similar slopes and Pzf were observed for the PFR of both total myocardial mass and subepicardial region at low and high Pcs. Subendocardial:subepicardial blood flow ratios increased for each set of measurements when Pcs was elevated (p less than 0.0001), owing to a reduction of subepicardial blood flow; however, subendocardial blood flow remained unchanged, while starting in the subepicardium toward midmyocardium blood flow decreased at high Pcs. This pattern was similar for the uninstrumented anterior wall as well as in the posterior wall. Thus as Pcs increases it becomes the effective coronary back pressure with decreasing magnitude from the subepicardium toward the subendocardium of the left ventricle. Assuming that elevating Pcs results in transmural elevation in coronary venous pressure, these findings support the hypothesis of a differential intramyocardial waterfall mechanism with greater subendo- than subepi-cardial tissue pressure.     

Increases in myocardial cyclic GMP attenuate contractile delay in myocardial stunning

We tested the hypothesis that the effects of myocardial stunning would be reduced by cyclic GMP in rabbit hearts. In three groups of anesthetized open-chest New Zealand white rabbits, myocardial stunning was produced by 15 min of occlusion of the left anterior descending coronary artery followed by 15 min of reperfusion repeated twice. Either control vehicle (saline plus 1% dimethyl sulfoxide) or 8-bromo-cyclic GMP (8-Br-cGMP (10(-4) and 10(-3) M)) was topically applied to the left ventricular surface. Hemodynamic (left ventricular and aortic pressures) and functional parameters (wall thickening, delay in onset of wall thickening, and rate of wall thickening) were determined. Coronary blood flow (microspheres) and O2 extraction (microspectrophotometry) were used to determine myocardial O2 consumption (VO2). Myocardial stunning was observed in the control group through an increased delay in onset of myocardial wall thickening (29 +/- 7 versus 55 +/- 16 ms) and decreased maximal rate of wall thickening (20 +/- 8 versus 11 +/- 3 mm x s(-1)). After treatment with 8-Br-cGMP 10(-4) and 10(-3) M, stunning did not increase the delay (37 +/- 5 versus 39 +/- 7 and 39 +/- 7 versus 28 +/- 8 ms). Myocardial stunning did not significantly alter VO2. 8-Br-cGMP 10(-3) M significantly decreased subepicardial VO2 (6.2 +/- 0.8 versus 3.7 +/- 0.6 mL O2 x min(-1) 100 g(-1)) and insignificantly decreased subendocardial VO2 (8.6 +/- 0.9 versus 6.3 +/- 1.2 mL O2 x min(-1) x 100 g(-1)) when compared with the vehicle-treated rabbits. We conclude that increasing cyclic GMP reduced the effects of myocardial stunning in the rabbit heart by ameliorating the delay in onset of wall thickening and decreasing the local O2 costs in the stunned region.     

Heterogeneous connexin43 expression produces electrophysiological heterogeneities across ventricular wall

Recently we found that electrophysiological (EP) heterogeneities between subepicardial and midmyocardial cells can form a substrate for reentrant ventricular arrhythmias. However, cell-to-cell coupling through gap junctions is expected to attenuate transmural heterogeneities between cell types spanning the ventricular wall. Because connexin43 (Cx43) is the principal ventricular gap junction protein, we hypothesized that transmural EP heterogeneities are in part produced by heterogeneous Cx43 expression across the ventricular wall. The left ventricles of eight dogs were sectioned to expose the transmural surface. To determine whether heterogeneous Cx43 expression influenced EP function, high-resolution transmural optical mapping of the arterially perfused canine wedge preparation was used to measure transmural conduction velocity (thetaTM), dV/dt(max), transmural space constant (lambdaTM), and transmural gradients of action potential duration (APD). Relative Cx43 expression, quantified by confocal immunofluorescence, was significantly lower (by 24 +/- 17%; P < 0.05) in subepicardial compared with deeper layers. Importantly, reduced subepicardial Cx43 was associated with transmural heterogeneities of EP function evidenced by selectively reduced subepicardial thetaTM (by 18 +/- 9%; P < 0.05) compared with deeper layers. In subepicardial regions, dV/dt(max) was fastest (by 19 +/- 15%) and lambdaTM was smallest (by 18.1 +/- 2%), which suggests that conduction slowing was attributable to localized uncoupling rather than reduced excitability. The maximum transmural APD gradients occurred in the same regions where Cx43 expression was lowest; this suggests that Cx43 expression patterns served to maintain APD gradients across the transmural wall. These data demonstrate that heterogeneous Cx43 expression is closely associated with functionally significant EP heterogeneities across the transmural wall. Therefore, Cx43 expression patterns can potentially contribute to arrhythmic substrates that are dependent on transmural electrophysiological heterogeneities.     

Diastolic dysfunction in volume-overload hypertrophy is associated with abnormal shearing of myolaminar sheets

Diastolic dysfunction in volume-overload hypertrophy by aortocaval fistula is characterized by increased passive stiffness of the left ventricle (LV). We hypothesized that changes in passive properties are associated with abnormal myolaminar sheet mechanics during diastolic filling. We determined three-dimensional finite deformation of myofiber and myolaminar sheets in the LV free wall of six dogs with cineradiography of implanted markers during development of volume-overload hypertrophy by aortocaval fistula. After 9 +/- 2 wk of volume overload, all dogs developed edema of extremities, pulmonary congestion, elevated LV end-diastolic pressure (5 +/- 2 vs. 21 +/- 4 mmHg, P < 0.05), and increased LV volume. There was no significant change in systolic function [dP/dt(max): 2,476 +/- 203 vs. 2,330 +/- 216 mmHg/s, P = not significant (NS)]. Diastolic relaxation was significantly reduced (dP/dt(min): -2,466 +/- 190 vs. -2,076 +/- 166 mmHg/s, P < 0.05; time constant of LV pressure decline: 32 +/- 2 vs. 43 +/- 1 ms, P < 0.05), whereas duration of diastolic filling was unchanged (304 +/- 33 vs. 244 +/- 42 ms, P = NS). Fiber stretch and sheet shear occur predominantly in the first third of diastolic filling, and chronic volume overload induced remodeling in lengthening of the fiber and reorientation of the laminar sheet architecture. Sheet shear was significantly increased and delayed at the subendocardial layer (P < 0.05), whereas magnitude of fiber stretch was not altered in volume overload (P = NS). These findings indicate that enhanced filling in volume-overload hypertrophy is achieved by enhanced sheet shear early in diastole. These results provide the first evidence that changes in motion of radially oriented laminar sheets may play an important functional role in pathology of diastolic dysfunction in this model.     

Impaired subendocardial contractile myofiber function in asymptomatic aged humans, as detected using MRI

With aging, structural and functional changes occur in the myocardium without obvious impairment of systolic left ventricular (LV) function. Transmural differences in myocardial vulnerability for these changes may result in increase of transmural inhomogeneity in contractile myofiber function. Subendocardial fibrosis and impairment of subendocardial perfusion due to hypertension might change the transmural distribution of contractile myofiber function. The ratio of LV torsion to endocardial circumferential shortening (torsion-to-shortening ratio; TSR) during systole reflects the transmural distribution of contractile myofiber function. We investigated whether the transmural distribution of systolic contractile myofiber function changes with age. Magnetic resonance tissue tagging was performed to derive LV torsion and endocardial circumferential shortening. TSR was quantified in asymptomatic young [age 23.2 (SD 2.6) yr, n = 15] and aged volunteers [age 68.8 (SD 4.4) yr, n = 16]. TSR and its standard deviation were significantly elevated in the aged group [0.47 (SD 0.12) aged vs. 0.34 (SD 0.05) young; P = 0.0004]. In the aged group, blood pressure and the ratio of LV wall mass to end-diastolic volume were mildly elevated but could not be correlated to the increase in TSR. There were no significant differences in other indexes of systolic LV function such as end-systolic volume and ejection fraction. The elevated systolic TSR in the asymptomatic aged subjects suggests that aging is associated with local loss of contractile myofiber function in the subendocardium relative to the subepicardium potentially caused by subclinical pathological incidents.     

Determinants of coronary microvascular dysfunction in symptomatic hypertrophic cardiomyopathy

Impaired hyperemic myocardial blood flow (MBF) in hypertrophic cardiomyopathy (HCM), despite normal epicardial coronary arteries, results in microvascular dysfunction. The aim of the present study was to determine the relative contribution of extravascular compressive forces to microvascular dysfunction in HCM. Eighteen patients with symptomatic HCM and normal coronary arteries and 10 age-matched healthy volunteers were studied with PET to quantify resting and hyperemic MBF at a subendocardial and subepicardial level. In HCM patients, MRI was performed to determine left ventricular (LV) mass index (LVMI) and volumes, echocardiography to assess diastolic perfusion time, heart catheterization to measure LV outflow tract gradient (LVOTG) and LV pressures, and serum NH(2)-terminal pro-brain natriuretic peptide (NT-proBNP) as a biochemical marker of LV wall stress. Hyperemic MBF was blunted in HCM vs. controls (2.26 +/- 0.97 vs. 2.93 +/- 0.64 ml min(-1) g(-1), P < 0.05). In contrast to controls (1.38 +/- 0.15 to 1.25 +/- 0.19, P = not significant), the endocardial-to-epicardial MBF ratio decreased significantly in HCM during hyperemia (1.20 +/- 0.11 to 0.88 +/- 0.18, P < 0.01). This pattern was similar for hypertrophied septum and lateral wall. Hyperemic MBF was inversely correlated with LVOTG, NT-proBNP, left atrial volume index, and LVMI (all P < 0.01). Multivariate regression analysis, however, revealed that only LVMI and NT-proBNP were independently related to hyperemic MBF, with greater impact at the subendocardial myocardial layer. Hyperemic MBF is more severely impaired at the subendocardial level in HCM patients. The level of impairment is related to markers of increased hemodynamic LV loading conditions and LV mass. These observations suggest that, in addition to reduced capillary density caused by hypertrophy, extravascular compressive forces contribute to microvascular dysfunction in HCM patients.     

Regional metabolic rate of exogenous glucose in the isoprenaline and dobutamine stimulated canine myocardium as estimated by the 2-deoxy-d[1-14C]glucose method

The effect of β-adrenoceptor stimulation by isoprenaline and dobutamine on the transmural distribution pattern of regional myocardial metabolic rate of exogenous glucose (RMMRGlc) was studied in the anesthetized closed chest dog using the 2-deoxy-d[1-¹⁴C]glucose method. In a previous series a lumped constant (LC) value of 0.93 ± 0.47 (1 SD) was measured for [¹⁴C]2-deoxyglucose in the canine myocardium. In the control group (N = 12) RMMRGlc was significantly higher in the subendocardial layer of the left ventricular free wall than in both the middle and subepicardial layer, where it was quite evenly distributed (P ⩽ 0.05). With i.v. dobutamine (N = 8) RMMRGlc was significantly lower in the midportion of left ventricular free wall than in the subepicardial layer (P ⩽ 0.05), but it was not different from the inner wall section. Significant differences between the subepicardial and subendocardial portions of the left ventricular free wall could not be found, either. In the isoprenaline group (N = 9) no transmural gradients of RMMRGlc were observed in the left ventricular myocardium. In all groups, both the interventricular septum and the right ventricular free wall exhibited homogeneous distribution patterns of RMMRGlc.It is concluded that transmural distribution patterns of exogenous glucose utilization probably reflect corresponding gradients in energy demands of the left ventricular wall. Redistribution of RMMRGlc in the isoprenaline and dobutamine groups may result from altered working conditions, a change in local inotropic state of the left ventricular myocardium, or from regional differences in the proportions of substrate utilization, and from regional differences in adrenoceptor density.     

Cardiac remodeling and functional adaptations consecutive to altitude training in rats: implications for sea level aerobic performance.

This study questioned the effect of living and training at moderate altitude on cardiac morphological and functional adaptations and tested the incidences of potential specific adaptations compared with aerobic sea level training on maximal left ventricular performance. Sea level-native rats were randomly assigned to N (living in normoxia), NT (living and training 5 days/wk for 5 wk in normoxia), CH (living in hypoxia, 2,800 m), and CHT (living and training 5 days/wk for 5 wk in hypoxia, 2,800 m) groups. Cardiac adaptations were evaluated throughout the study period by Doppler echocardiography. Maximal stroke volume (LV(SVmax)) was measured during volume overloading before and after the study period. Finally, at the end of the study period, passive pressure-volume relationships on isolated heart and cardiac weighing were obtained. Altitude training resulted in a specific left ventricular (LV) remodeling compared with NT, characterized by an increase in wall thicknesses without any alteration in internal dimensions. These morphological adaptations associated with hypoxia-induced alterations in pulmonary outflow and preload conditions led to a decrease in LV filling and subsequently no improvement in LV performance during resting physiological conditions in CHT compared with NT. Such a lack of improvement was confirmed during volume overloading that simulated maximal effort (LV(SVmax) pretest: NT = 0.58 +/- 0.05, CHT = 0.57 +/- 0.08 ml; posttest: NT = 0.72 +/- 0.06, CHT = 0.58 +/- 0.07 ml; NT vs. CHT in posttest session, P < 0.05). Maximal aerobic velocities increased to the same extent in NT and CHT rats despite marked polycythemia in the latter. The lack of LV(SVmax) improvement resulting from altitude training-induced cardiac morphological and functional adaptations could be responsible for this phenomenon.     

Optical measurements reveal nature of intercellular coupling across ventricular wall

Previously, we showed that intercellular uncoupling through gap junctions is an important mechanism for maintaining transmural heterogeneities of repolarization that are responsible for ventricular arrhythmias in disease states such as heart failure. However, rotational anisotropy between transmural muscle layers also may influence coupling. To determine the effect of rotational anisotropy on transmural coupling, we developed a numerical three-dimensional model of passive cardiac tissue in which rotational anisotropy was varied in a controlled fashion. Simulations of optical mapping demonstrated that spatial averaging produced a voltage decay in space best fit by a single decaying exponential compared with the theoretically predicted decay. As fiber orientation varied by 90 degrees with respect to the transmural surface, the effective transmural space constant (lambda(TM)) changed by only 0.31% in simulations. In contrast, reducing intercellular conductivity by 24% decreased lambda(TM) by 7.7%. In the canine wedge preparation (n = 5), lambda measured by optical mapping of the epicardial and subepicardial surface was similar transverse (lambda(TV) = 0.73 +/- 0.10 mm) and transmural (lambda(TM) = 0.70 +/- 0.08 mm) to subepicardial fibers. We confirmed previous findings that lambda(TM) in subepicardial layers was significantly reduced by 14 +/- 2% compared with deeper layers of myocardium, providing evidence for transmural uncoupling in the epicardial-midmyocardial interface. These data establish the theoretical and experimental basis for measuring intercellular coupling between muscle layers spanning the ventricular wall with optical mapping techniques. Furthermore, this study demonstrates that transmural uncoupling at the epicardial-midmyocardial interface may be attributable to heterogeneous expression of cardiac gap junctions and not rotational anisotropy.