Glen A. Laine

Left ventricular myocardial edema. Lymph flow, interstitial fibrosis, and cardiac function.

We hypothesized that both acute and chronic accumulation of myocardial interstitial edema (extravascular fluid [EVF]) would compromise cardiac function. We also postulated that excess fluid within the myocardial interstitial space would potentiate interstitial fibrosis, thus further compromising function. Dogs were divided into three groups: 1) control, 2) chronic pulmonary hypertensive with right heart failure, and 3) chronic arterial hypertensive. The quantity of EVF, expressed as the unitless blood-free (wet weight-dry weight)/dry weight ratio, and interstitial fibrosis (collagen content) were determined and correlated with cardiac function at baseline and after acute elevation of coronary venous pressure and reduction of cardiac lymph flow. Control EVF was 2.90 +/- 0.20 (mean +/- SD), which increased to 3.45 +/- 0.16 after acute (3-hour) elevation of coronary sinus pressure. This EVF significantly compromised cardiac function. The EVF in chronically hypertensive dogs and in dogs with chronic right heart pressure elevations was 3.50 +/- 0.30 and 3.50 +/- 0.08, respectively. End-diastolic left ventricular interstitial fluid pressure increased from a control value of 14.9 +/- 3.1 (at EVF = 2.9) to 24.8 +/- 3.7 (at EVF = 3.5). An EVF of 3.5 produced approximately 30% reduction of the hearts ability to maintain cardiac output at a left atrial pressure of 15 mm Hg. The compromised function in these chronic models is exacerbated after acute elevation of coronary venous pressure and reduction of cardiac lymph flow. Collagen levels were elevated by at least 20% in the chronic hypertensive dogs and in the nonhypertrophied left ventricles of dogs with chronic right heart pressure elevation.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial fluid balance

Fluid accumulation in the cardiac interstitium or myocardial edema is a common manifestation of many clinical states. Specifically, cardiac surgery includes various interventions and pathophysiological conditions that cause or worsen myocardial edema including cardiopulmonary bypass and cardioplegic arrest. Myocardial edema should be a concern for clinicians as it has been demonstrated to produce cardiac dysfunction. This article will briefly discuss the factors governing myocardial fluid balance and review the evidence of myocardial edema in various pathological conditions. In particular, myocardial microvascular, interstitial, and lymphatic interactions relevant to the field of cardiac surgery will be emphasized.

Resuscitation-induced gut edema and intestinal dysfunction

BACKGROUNDnMesenteric venous hypertension and subsequent gut edema play a pivotal role in the development of intra-abdominal hypertension. Although gut edema is one cause of intra-abdominal hypertension, its impact on gut function is unknown. The purpose of this study was to create a model of acute hydrostatic gut edema and to evaluate its effect on gut motility and barrier function.nnnMETHODSnThe first study, group A, evaluated the effect of gut edema on transit over time using 20 mL/kg 0.9% saline. The second study, group B, focused on the 12-hour time period using 80 mL/kg 0.9% saline. Rats were randomized to superior mesenteric vein partial occlusion (venous hypertension) or sham surgery. At 6, 12, and 24 hours, group A underwent intestinal transit and tissue water weight measurements. At 12 hours, group B underwent tissue water, transit, ileal permeability and resistance, lactate and myeloperoxidase activity, and mucosal injury measurements.nnnRESULTSnVenous hypertension with fluid resuscitation caused acute hydrostatic gut edema, delayed intestinal transit, increased mucosal permeability to macromolecules, and decreased tissue resistance over time. Mucosal injury was minimal in mesenteric venous hypertension.nnnCONCLUSIONnAcute mesenteric venous hypertension and resuscitation-induced gut edema, in the absence of ischemia/reperfusion injury, is associated with delayed intestinal transit and altered gut barrier function.

Outflow pressure reduces lymph flow rate from various tissues

We previously reported that the very act of cannulating a lung lymph vessel could alter the unique flow characteristics that existed within the lymphatic before cannulation. We postulated that this phenomenon could hold true for lymphatics draining any organ within the body. Since it is frequently important to know the relationship between the transmicrovascular fluid flux and true lymph flow rate, it would be critical that a cannulated lymphatic vessel have the same flow characteristics as those uncannulated vessels draining the same organ. In order to test our hypothesis we cannulated lymph vessels draining the heart, liver, small intestine, kidney, and skeletal muscle. By altering the lymphatic outflow pressure (normally related to systemic venous pressure) and by using lymphatic cannulas of various resistance, we were able to demonstrate that lymph flow varied linearly with lymphatic outflow pressure in every organ. By increasing transmicrovascular fluid flux and lymph flow rate in each organ we were also able to demonstrate that effective resistance of the lymphatic vessels and the effective pressure driving lymph flow varied as a function of the physical characteristics of the organ under investigation. Characteristic effective resistances of the heart, liver, skeletal muscle, kidney, and small intestine lymphatics decreased by 83, 40, 61, 36, and 50%, respectively. Along with these changes in effective resistance, the effective lymph driving pressure in the same organs varied by 49, 0, 257, 0, and 63%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Microvascular changes in the heart during chronic arterial hypertension.

Changes of myocardial micro vascular permeability in chronic renovascular arterial hypertension were studied. Hypertension was induced in dogs utilizing a one-kidney, one-clip Goldblatt model. Systemic arterial pressure, coronary sinus pressure, systemic venous pressure, myocardial lymph flow rate, myocardial interstitial fluid pressure, and the lymph-to-plasma protein concentration ratio for total plasma proteins and for p-lipoprotein (CL/CP) were determined in control animals and 4-6 weeks following the Goldblatt procedure in hypertensive animals. Control values for the normotensive animals were 123 ± 17 mm Hg, 7.3 ±1.3 mm Hg, 2.5 ±2.1 mm Hg, 3.1 ± 2.1 ml/hr, 14.9 ± 3.1 mm Hg, 0.82, and 0.33, respectively, while control values for the chronically hypertensive dogs were 160 ±20 mm Hg, 7.8 ±1.9 mm Hg, 2.9 ±2.5 mm Hg, 10.5 ±2.5 ml/hr, 24.8 ±3.7 mm Hg, 0.87, and 0.31, respectively. Under control conditions, myocardial lymph flow rate was significantly higher in the hypertensive group while no difference could be demonstrated in (CL/CP) between the two groups. This is indicative of either a change in myocardial microvascular permeability or an increase in microvascular exchange surface area. Coronary sinus pressure was elevated in both groups in order to increase transmicrovascular fluid flux and determine the nitration-independent reflection coefficient (s`) for each group, a is a surface area-independent indicator of microvascular permeability when determined for specific protein molecules at high transmicrovascular fluid fluxes. Although filtration independence for total plasma protein could not be reached in either group, s` for β-lipoprotein decreased from 0.96 in the normotensive group to 0.80 in the hypertensive group, indicating an increase in microvascular permeability. Our results indicate a significant increase in myocardial microvascular permeability to macromolecules resulting from the one-kidney, one-clip Goldblatt model of chronic arterial hypertension.

Hypertonic saline modulation of intestinal tissue stress and fluid balance.

Crystalloid-based resuscitation of severely injured trauma patients leads to intestinal edema. A potential mechanism of intestinal edema-induced ileus is a reduction of myosin light chain phosphorylation in intestinal smooth muscle. We sought to determine if the onset of edema initiated a measurable, early mechanotransductive signal and if hypertonic saline (HS) can modulate this early signal by changing intestinal fluid balance. An anesthetized rat model of acute interstitial intestinal edema was used. At laparotomy, the mesenteric lymphatic was cannulated to measure lymph flow and pressure, and a fluid-filled micropipette was placed in the intestinal submucosa to measure interstitial pressure. Rats were randomized into four groups (n = 6 per group): sham, mesenteric venous hypertension + 80 mL/kg 0.9% isotonic sodium chloride solution (ISCS 80), mesenteric venous hypertension + 80 mL/kg 0.9% ISCS + 4 mL/kg 7.5% saline (ISCS 80 + HS), or 4 mL/kg 7.5% saline (HS alone) to receive the aforementioned intravenous fluid administered over 5 min. Measurements were made 30 min after completion of the preparation. Tissue water, lymph flow, and interstitial pressure were measured. Resultant applied volume induced stress on the smooth muscle (σravi-muscularis) was calculated. Mesenteric venous hypertension and crystalloid resuscitation caused intestinal edema that was prevented by HS. Intestinal edema caused an early increase in intestinal interstitial pressure that was prevented by HS. Hypertonic saline did not augment lymphatic removal of intestinal edema. σravi-muscularis was increased with onset of edema and prevented by HS, paralleling the interstitial pressure data. Intestinal edema causes an early increase in interstitial pressure that is prevented by HS. Prevention of the edema-induced increase in interstitial pressure serves to blunt the mechanotransductive signal of σravi-muscularis.

A model of the lung interstitial-lymphatic system

Our model of the pulmonary interstitial-lymphatic system is based on the assumption that the lung interstitial space can be divided into two compartments. The first compartment (C1) contains the terminal lymph vessels. Increases in the fluid pressure within this compartment, along with increased pressure generated by lymph vessel pumping, cause the lymph flow rate to increase. The lymph vessels run through the second compartment (C2) which we believe represents the perivascular spaces. Increases in the fluid volume of C2 cause the lymph vessels to dilate and this causes lymph vessel resistance to decrease. Normally the lymph flow rate equals the microvascular filtration rate so that lung fluid volume is constant. According to our model, increases in filtration rate cause fluid to collect in C1 and C2. The resulting increase in fluid pressure in C1, increased lymph vessel pumping, and the decrease in lymph vessel resistance in C2 cause lymph flow to increase. Eventually, the lymph flow rises to equal the filtration rate and lung fluid volume becomes constant again. The results of simulations with our model indicate that decreases in lymph vessel resistance are essential for lymph flow to increase substantially as edema develops.

Pressure within the thoracic duct modulates lymph composition

The amount of lymph received by the thoracic duct depends on each contributing organs ability to produce interstitial fluid and generate a pressure differential moving lymph into the central lymphatic circulation. It has been reported that varying the pressure within the thoracic duct could alter each organs contribution to thoracic duct flow. The thoracic duct above the diaphragm was cannulated to obtain lymph from the liver, gut, and lower body. Pressure within the thoracic duct was elevated serially by increasing the lymphatic cannula outflow height. This caused lymph protein concentration to increase while chyle concentration (measured by absorbance) decreased. The data demonstrate that as thoracic duct pressure increases, the percentage contribution of gut lymph flow (as represented by chyle concentration) decreases while the contribution of lymph originating within the liver (as indicated by higher protein concentration) increases. We conclude that pressure variation within the central lymphatic system affects the amount of lymph or edema fluid leaving any given organ.

Sodium hydrogen exchanger as a mediator of hydrostatic edema-induced intestinal contractile dysfunction

BACKGROUNDnResuscitation-induced intestinal edema is associated with early and profound mechanical changes in intestinal tissue. We hypothesize that the sodium hydrogen exchanger (NHE), a mechanoresponsive ion channel, is a mediator of edema-induced intestinal contractile dysfunction.nnnMETHODSnAn animal model of hydrostatic intestinal edema was used for all experiments. NHE isoforms 1-3 mRNA and protein were evaluated. Subsequently, the effects of NHE inhibition (with 5-(N-ethyl-N-isopropyl) amiloride [EIPA]) on wet-to-dry ratios, signal transduction and activator of transcription (STAT)-3, intestinal smooth muscle myosin light chain (MLC) phosphorylation, intestinal contractile activity, and intestinal transit were measured.nnnRESULTSnNHE1-3 mRNA and protein levels were increased significantly in the small intestinal mucosa with the induction of intestinal edema. The administration of EIPA, an NHE inhibitor, attenuated validated markers of intestinal contractile dysfunction induced by edema as measured by decreased STAT-3 activation, increased MLC phosphorylation, improved intestinal contractile activity, and enhanced intestinal transit.nnnCONCLUSIONnThe mechanoresponsive ion channel NHE may mediate edema-induced intestinal contractile dysfunction, possibly via a STAT-3 related mechanism.