Testicular hyperthermia increases blood flow that maintains aerobic metabolism in rams.

There is a paradigm that testicular hyperthermia fails to increase testicular blood flow and that an ensuing hypoxia impairs spermatogenesis. However, in our previous studies, decreases in normal and motile spermatozoa after testicular warming were neither prevented by concurrent hyperoxia nor replicated by hypoxia. The objective of the present study was to determine the effects of increasing testicular temperature on testicular blood flow and O2 delivery and uptake and to detect evidence of anaerobic metabolism. Under general anaesthesia, the testicular temperature of nine crossbred rams was sequentially maintained at ~33°C, 37°C and 40°C (±0.5°C; 45min per temperature). As testicular temperature increased from 33°C to 40°C there were increases in testicular blood flow (13.2±2.7 vs 17.7±3.2mLmin-1 per 100g of testes, mean±s.e.m.; P<0.05), O2 extraction (31.2±5.0 vs 47.3±3.1%; P<0.0001) and O2 consumption (0.35±0.04 vs 0.64±0.06mLmin-1 per 100g of testes; P<0.0001). There was no evidence of anaerobic metabolism, based on a lack of change in lactate, pH, HCO3- and base excess. In conclusion, these data challenge the paradigm regarding scrotal-testicular thermoregulation, as acute testicular hyperthermia increased blood flow and tended to increase O2 delivery and uptake, with no indication of hypoxia or anaerobic metabolism.

Increased testicular blood flow maintains oxygen delivery and avoids testicular hypoxia in response to reduced oxygen content in inspired air.

Despite a long-standing assertion that mammalian testes operate near hypoxia and increased testicular temperature causes frank hypoxia, we have preliminary evidence that changes are due to hyperthermia per se. The objective was to determine how variations in inspired oxygen concentration affected testicular blood flow, oxygen delivery and extraction, testicular temperature and lactate production. Eight rams were maintained under general anesthesia, with successive decreases in oxygen concentration in inspired air (100, 21 and 13%, respectively). As oxygen concentration decreased from 100 to 13%, there were increases in testicular blood flow (9.6 ± 1.7 vs 12.9 ± 1.9 ml/min/100 g of testis, P < 0.05; mean ± SEM) and conductance (normalized flow; 0.46 ± 0.07 to 1.28 ± 0.19 ml/min/mm Hg/100 g testis (P < 0.05). Increased testicular blood flow maintained oxygen delivery and increased testicular temperature by ~1 °C; this increase was correlated to increased testicular blood flow (r = 0.35, P < 0.0001). Furthermore, oxygen utilization increased concomitantly and there were no significant differences among oxygen concentrations in blood pH, HCO3- or base excess, and no effects of venous-arterial differences in lactate production. In conclusion, under acute hypoxic conditions, testes maintained oxygen delivery and uptake by increasing blood flow and oxygen extraction, with no evidence of anaerobic metabolism. However, additional studies are needed to determine longer-term responses and potential evidence of anaerobic metabolism at the molecular level.

Endografting of the descending thoracic aorta increases ascending aortic input impedance and attenuates pressure transmission in dogs.

OBJECTIVES: Endografting is being used to manage aneurysms, dissections and acute traumatic disruptions of the thoracic aorta. The acute effects of such interventions on ventricular afterload and on pressure wave transmission characteristics are not well known. METHODS: In five dogs, a 55 mm endograft was introduced into the descending aorta, just distal to the left subclavian artery, with oversizing of 20%. Following formaldehyde induced complete heart block, the hearts were paced (30-120bpm). The ascending aortic pressures and flows were recorded using Millar micro-tip manometers and ultrasonic flowmeters, respectively. Arterial pressures proximal and distal to the stent site were also recorded. For each heart rate, parameters of a modified Windkessel (SVR: systemic vascular resistance, Z0: characteristic impedance, C: total arterial compliance) were estimated. The pulse wave velocity (PWV) and reflection coefficient (Gamma) were calculated from the pressure wave transfer functions. RESULTS: The Z0 (0.25+/-0.05 vs 0.41+/-0.06 mmHg/ml s(-1), P<.05) was increased and C was decreased (0.45+/-0.07 vs 0.28+/-0.04 ml/mmHg, P<0.001) following endograft placement. SVR tended to increase (P=.06) and ascending aortic Gamma was unchanged. The PWV increased (418+/-67 vs 755+/-135 cm/s, P<.05) and the distal Gamma decreased (0.09+/-0.10 vs -0.49+/-0.07, P<.05). CONCLUSIONS: Endografting in the proximal descending aorta cause unfavorable changes in the ascending aortic input impedance and an increase in the PWV through the grafted segment, consistent with an increase in the modulus of elasticity. The grafts produce a negative Gamma at the distal end, an uncommon occurrence in the systemic circulation. Whether this change is of sufficient magnitude to result in post-graft dilation is unknown.

The effect of a venous filter on the embolic load during medullary canal pressurization: a canine study.

BACKGROUND: Acute intramedullary stabilization of femoral shaft fractures in multiply injured patients is controversial. Intravasation of medullary fat during canal pressurization has been suspected to trigger adult respiratory distress syndrome. The goal of the present study was to evaluate the effect, on the lungs, of a filter placed into the ipsilateral common iliac vein during medullary canal pressurization in a canine model. METHODS: With use of an established model of fat embolization, twelve mongrel dogs were randomized into two groups. In six dogs, a special filter was inserted percutaneously into the left common iliac vein while the dogs were under general anesthesia. In all dogs, the left femur and tibia were then pressurized by injection of bone cement and insertion of intramedullary rods. Hemodynamic measurements and echocardiographic images were recorded throughout the experiment. After one hour, the animals were killed and the lungs were harvested for histomorphometric analysis. RESULTS: Without the filter, the mean pulmonary artery pressure increased by 11.8 +/- 2.1 mm Hg (p < 0.001). With the filter, the mean pulmonary artery pressure increased by only 2.2 +/- 0.8 mm Hg (p < 0.02). Without the filter, there was a significant increase in the index of pulmonary vascular resistance as compared with the baseline value (p < 0.05). With the filter, there was no such increase. Histomorphometric analysis demonstrated that the presence of the filter reduced the absolute area of embolization and the volume percentages of lung and pulmonary vasculature embolized. CONCLUSIONS: In this canine experiment, temporary placement of a venous filter prior to medullary canal pressurization reduced the embolic load and minimized its hemodynamic effects.

Left ventricular pacing minimizes diastolic ventricular interaction, allowing improved preload-dependent systolic performance.

BACKGROUND: Left ventricular (LV) pacing improves hemodynamics in patients with heart failure. We hypothesized that at least part of this benefit occurs by minimization of external constraint to LV filling from ventricular interaction. METHODS AND RESULTS: We present median values (interquartile ranges) for 13 heart failure patients with LV pacing systems implanted for New York Heart Association class III/IV limitation. We used the conductance catheter method to measure LV pressure and volume simultaneously. External constraint was measured from the end-diastolic pressure-volume relation recorded during inferior vena caval occlusion, during LV pacing, and while pacing was suspended. External constraint to LV filling was reduced by 3.0 (4.6 to 0.6) mm Hg from 4.8 (0.6 to 7.5) mm Hg (P<0.01) in response to LV pacing; effective filling pressure (LV end-diastolic pressure minus external constraint) increased by 4.0 (2.2 to 5.8) mm Hg from 17.7 (13.3 to 22.6; P<0.01). LV end-diastolic volume increased by 10 (3 to 11) mL from 238 (169 to 295) mL (P=0.01), whereas LV end-systolic volume did not change significantly (-1 [-2 to 3] mL from 180 [124 to 236] mL, P=0.97), which resulted in an increase in stroke volume of 11 (5 to 13) mL from 49 (38 to 59) mL (P<0.01). LV stroke work increased by 720 (550 to 1180) mL . mm Hg from 3400 (2110 to 4480) mL . mm Hg (P=0.01), and maximum dP/dt increased by 120 (2 to 161) mm Hg/s from 635 (521 to 767) mm Hg/s (P=0.03). CONCLUSIONS: This study suggests a potentially important mechanism by which LV pacing may produce hemodynamic benefit. LV pacing minimizes external constraint to LV filling, resulting in an increase in effective filling pressure; the consequent increase in LV end-diastolic volume increases stroke volume via the Starling mechanism.

Ventricular interaction and external constraint account for decreased stroke work during volume loading in CHF.

The slope of the stroke work (SW)-pulmonary capillary wedge pressure (PCWP) relation may be negative in congestive heart failure (CHF), implying decreased contractility based on the premise that PCWP is simply related to left ventricular (LV) end-diastolic volume. We hypothesized that the negative slope is explained by decreased transmural LV end-diastolic pressure (LVEDP), despite the increased LVEDP, and that contractility remains unchanged. Rapid pacing produced CHF in six dogs. Hemodynamic and dimension changes were then measured under anesthesia during volume manipulation. Volume loading increased pericardial pressure and LVEDP but decreased transmural LVEDP and SW. Right ventricular diameter increased and septum-to-LV free wall diameter decreased. Although the slopes of the SW-LVEDP relations were negative, the SW-transmural LVEDP relations remained positive, indicating unchanged contractility. Similarly, the SW-segment length relations suggested unchanged contractility. Pressure surrounding the LV must be subtracted from LVEDP to calculate transmural LVEDP accurately. When this was done in this model, the apparent decrease in contractility was no longer evident. Despite the increased LVEDP during volume loading, transmural LVEDP and therefore SW decreased and contractility remained unchanged.

Left ventricular wave speed.

Left ventricular (LV) wave speed (LVWS) was studied experimentally and confirmed in theory. Combining the definition of elastance (E) with the equations for the conservation of mass and momentum shows that LVWS is proportional to the square root of ELA, where L is long-axis length and A is the cross-sectional area, and the density of the blood. (We defined ELA = gamma, where gamma is compressibility.) We studied nine open chest, anesthetized dogs, three of which were studied during caval constriction when LV end-diastolic pressure was < or =0 mmHg. The hearts were paced at approximately 90 beats/min, and LV cross-sectional area was measured by using two pairs of ultrasonic crystals; E was calculated from the LV pressure-area loop. A pulse generator was connected to the LV apex, and LVWS was measured by using two pressure transducers: one near the apex and the other near the base. Their distance was measured roentgenographically and compared with the diameter of a reference ball. LVWS ranged from approximately 1 m/s during diastole to approximately 10 m/s during systole. The slope of the log c (where c is wave speed) vs. log gamma was 0.546, which is in agreement with theory (0.5). When gamma < or = 0, LVWS was approximately 1.5 m/s.

Left ventricular stroke volume in the fetal sheep is limited by extracardiac constraint and arterial pressure.

1. Extracardiac constraint and sensitivity to arterial pressure may be critical factors that limit the functional reserves of the developing fetal heart in utero. We hypothesise that extracardiac constraint is the predominant factor that limits fetal stroke volume (SV). To test this hypothesis we studied six chronically instrumented fetal sheep to determine the relative roles that extracardiac constraint and arterial pressure play in determining left ventricular (LV) function. 2. Pregnant ewes (128-131 days gestation, term = 147 days) were anaesthetised (5 mg kg(-1) Propofol I.V., then 1.5 % halothane, 50 % O(2), balance N(2)O by inhalation) and instrumented using sterile surgical techniques to record LV end-diastolic pressure (P(lved)), aortic pressure (P(ao)), pericardial pressure (P(per)), and LV SV. 3. After a minimum of 72 h recovery, LV function was assessed by altering fetal blood volume to vary P(lved). Ventricular function curves were generated using two measures of ventricular function, SV and stroke work index (SWI = SV x P(ao)), and two measures of ventricular filling, P(lved) and LV end-diastolic transmural pressure (P(lved,tm) = P(lved) - P(per)). 4. Although decreasing P(lved) from the resting level decreased SV, increasing P(lved) from the resting level did not increase SV because the ventricular function curve plateaued. This plateau was not explained solely by an increase in aortic pressure, as the plateau remained present in the SWI versus P(lved) curve. When extracardiac constraint was accounted for (SV against P(lved,tm)), the plateau was largely eliminated (approximately 80 %). The remaining portion of the plateau (approximately 20 %) was eliminated when both extracardiac constraint and arterial pressure were accounted for (SWI versus P(lved,tm)). 5. Thus, the major limitation upon LV function in the near-term fetus results from extracardiac constraint limiting ventricular filling while, at the same time, a much smaller limitation arises from increasing arterial pressure.

Negative wave reflections in pulmonary arteries.

The pulmonary arterial branching pattern suggests that the early systolic forward-going compression wave (FCW) might be reflected as a backward-going expansion wave (BEW). Accordingly, in 11 open-chest anesthetized dogs we measured proximal pulmonary arterial pressure and flow (velocity) and evaluated wave reflection using wave-intensity analysis under low-volume, high-volume, high-volume + 20 cmH2O positive end-expiratory pressure (PEEP), and hypoxic conditions. We defined the reflection coefficient R as the ratio of the energy of the reflected wave (BEW [-]; backward-going compression wave, BCW [+]) to that of the incident wave (FCW [+]). We found that R = -0.07 +/- 0.02 under low-volume conditions, which increased in absolute magnitude to -0.20 +/- 0.04 (P < 0.01) under high-volume conditions. The addition of PEEP increased R further to -0.26 +/- 0.02 (P < 0.01). All of these BEWs were reflected from a site ~3 cm downstream. During hypoxia, the BEW was maintained and a BCW appeared (R = +0.09 +/- 0.03) from a closed-end site ~9 cm downstream. The normal pulmonary arterial circulation in the open-chest dog is characterized by negative wave reflection tending to facilitate right ventricular ejection; this reflection increases with increasing blood volume and PEEP.

Ventricular interaction: from bench to bedside.

Decreased right ventricle (RV) output results in decreased left ventricle end-diastolic volume (LVEDV) and output by series interaction. Direct ventricular interaction may also have a major effect on LV function. Thus, decreased LVEDV caused by reduced RV output may be further reduced by a leftward septal shift and pericardial constraint. This has been shown to be true in acute and chronic pulmonary hypertension and is now also apparent in severe congestive heart failure. The use of intracavitary LV end-diastolic pressure (LVEDP) to assess LVEDV is inappropriate if pressure surrounding the LV is increased: the surrounding pressure should be subtracted from LVEDP to calculate the effective distending (transmural) pressure which governs preload. If the surrounding pressure increases more than LVEDP, transmural LVEDP and LVEDV will decrease despite the increased LVEDP. Thus, the use of filling pressure to reflect changes in LVEDV has led to erroneous conclusions regarding changes in myocardial compliance and contractility. It is now clear that volume loading may reduce LVEDV and stroke work in pulmonary embolism, chronic lung disease and severe congestive heart failure despite increased LVEDP. The decreased stroke work is a result of reduced LV preload, not decreased contractility as would be suggested if filling pressure is used to reflect preload.

A 2D finite element model of the interventricular septum under normal and abnormal loading.

The interventricular septum is the structure that separates the left and right ventricles of the heart. Under normal loading conditions, it is concave to the left ventricle, but under abnormal loading the septum flattens and occasionally inverts. In the past, the septum has frequently been modelled as integral to the left ventricle with the effects of pressure from the right ventricle being ignored. Under abnormal loading, the septum has been described as behaving equivalent to a "flapping sail". There has been no consideration of structural behaviour under these conditions. A 2-D plane stress FE model of the septum was used to investigate the difference in structural behaviour of the septum during diastole between normal and abnormal loading. The biaxial stress patterns that develop are distinctively disparate. Under normal loading, the septum behaves much like a thick-walled cylinder subject to internal and external pressure, with the resulting stresses being circumferential tension and radial compression, both varying with radius. These stresses are very low throughout most of diastole. However, under abnormal loading, the septum behaves in an arch-like fashion, with high compressive stresses almost circumferential in direction, combined with radial compression. We conclude that right ventricular pressures cause bending effects in the wall of the heart, and that under abnormal loading, the compressive stresses that develop in the septum may lead to an understanding of certain, previously unexplained, pathological conditions.

Compression of interventricular septum during right ventricular pressure loading.

The interventricular septum, which flattens and inverts in conditions such as pulmonary hypertension, is considered by many to be an unstressed membrane, in that its position is assumed to be determined solely by the transseptal pressure gradient. A two-dimensional finite element model was developed to investigate whether compression and bending moments (behavior incompatible with a membrane) exist in the septum during diastole under abnormal loading, i.e., pulmonary artery (PA) constriction. Hemodynamic and echocardiographic data were obtained in six open-chest anesthetized dogs. For both control and PA constriction, the measured left ventricular and right ventricular pressures were applied to a residually stressed mesh. Adjustments were made to the stiffness and end-bending moments until the deformed and loaded residually stressed mesh matched the observed configuration of the septum. During PA constriction, end-bending moments were required to obtain satisfactory matches but not during control. Furthermore, substantial circumferential compressive stresses developed during PA constriction. Such stresses might impede septal blood flow and provoke the unexplained ischemia observed in some conditions characterized by abnormal septal motion.

A novel technique for measurement of pericardial pressure.

To determine whether pericardial liquid pressure accurately measures pericardial constraint, we developed a technique in which a catheter was positioned perpendicular to the epicardial surface. This device, which occupies little or no pericardial space, couples the thin film of liquid to a transducer. In six open-chest dogs, we also measured left ventricular (LV) end-diastolic pressure (LVEDP) and anteroposterior and septum-to-free wall diameters. LVEDP was raised incrementally to approximately 25 mmHg by saline infusion. With the use of the product of the two diameters as an index of area (A(LV)), LVEDP-A(LV) relationships were obtained with the pericardium closed and again after the pericardium had been widely opened to obtain the isovolumic difference in LVEDP (DeltaLVEDP). In all dogs, the technique yielded values of pericardial pressure equal to DeltaLVEDP as well as equal to that measured using a previously placed balloon transducer in the same location and at the same A(LV). We conclude that, when the pressure of the pericardial liquid is appropriately measured, it (in addition to the balloon-measured contact stress) defines the diastolic constraining effect of the pericardium. Furthermore, we suggest that earlier measurements of pericardial "liquid pressure" were low, due to an artifact of measurement.

Static and dynamic operating characteristics of a pericardial balloon.

Previously, we developed a balloon transducer to measure the constraint of the pericardium (i.e., pericardial pressure) on the surface of the heart. It was validated physiologically in that it was shown to measure a pressure equal to the difference between the left ventricular end-diastolic pressure measured before and after pericardiectomy at the same left ventricular volume. To define its static operating characteristics, we loaded the balloon nonuniformly with weights that covered fractions of the balloon surface and found that the balloon accurately recorded the average stress if the stress was applied over at least 23% of its surface. To test its performance when curved, we placed it in large and small cylinders (minimum diameter 31 mm) and found that the balloon accurately recorded the stress. To define its dynamic operating characteristics, we applied sinusoidal stresses and found that its frequency response was limited only by that of the connecting catheter. When better dynamic response is required, we introduce a micromanometer-tipped catheter to obtain a unity-gain frequency response that is flat to 200 Hz.

Wave-intensity analysis: a new approach to coronary hemodynamics.

In 10 anesthetized dogs, we measured high-fidelity left circumflex coronary (P(LCx)), aortic (P(Ao)), and left ventricular (P(LV)) pressures and left circumflex velocity (U(LCx); Doppler) and used wave-intensity analysis (WIA) to identify the determinants of P(LCx) and U(LCx). Dogs were paced from the right atrium (control 1) or right ventricle by use of single (control 2) and then paired pacing to evaluate the effects of left ventricular contraction on P(LCx) and U(LCx). During left ventricular isovolumic contraction, P(LCx) exceeded P(Ao), paired pacing increasing the difference. Paired pacing increased DeltaP(X) (the P(LCx)-P(Ao) difference at the P(Ao)-P(LV) crossover) and average dP(LCx)/dt (P < 0.0001 for both). During this time, WIA identified a backward-going compression wave (BCW) that increased P(LCx) and decreased U(LCx); the BCW increased during paired pacing (P < 0.0001). After the aortic valve opened, the increase in P(Ao) caused a forward-going compression wave that, when it exceeded the BCW, caused U(LCx) to increase, despite P(LV) and (presumably) elastance continuing to increase. Thus WIA identifies the contributions of upstream (aortic) and downstream (microcirculatory) effects on P(LCx) and U(LCx).

Pericardial pressure in experimental chronic heart failure.

BACKGROUND: In the normal heart, pericardial pressure is greater than previously believed. OBJECTIVES: To explore the contribution of pericardial constraint to the elevated left ventricular (LV) end-diastolic pressure in chronic heart failure (CHF). ANIMALS AND METHODS: Pericardial pressure was measured directly in 11 dogs with CHF. Seven dogs were instrumented with LV and right ventricular micromanometers and epicardial pacing leads, and paced at 240 to 260 beats/min for four to seven weeks. After the development of CHF, a left thoracotomy was performed and a flat pericardial balloon was positioned over the LV free wall through a slit in the pericardium. RESULTS: LV end-diastolic pressure was 31+/-9 mmHg, and pericardial pressure only 7+/-2 mmHg. Nitroglycerin in six dogs decreased LV end-diastolic pressure from 33+/-8 to 28+/-7 and pericardial pressure from 7+/-2 to 6+/-3 mmHg (both P<0.05). Calculated transmural LV end-diastolic pressure also decreased (26+/-8 to 22+/-7 mmHg, P<0.05). Volume loading in five dogs increased LV end-diastolic pressure from 29+/-8 to 42+/-10 mmHg (P<0.05), pericardial pressure from 6+/-3 to 12+/-6 mmHg (not significant) and transmural LV end-diastolic pressure from 23+/-7 to 30+/-7 mmHg (not significant). When the pericardium was opened in three dogs, the LV end-diastolic pressure decreased by 5 mmHg. Four previously uninstrumented dogs were studied to exclude the effects of epicardial scarring; LV end-diastolic pressure was 42+/-6 mmHg and pericardial pressure was 10+/-6 mmHg. CONCLUSION: Pericardial constraint, a prerequisite for pericardially mediated ventricular interaction, was not present to the same extent in this model of CHF as in acute models, probably reflecting the importance of pericardial remodelling.

Effects of positive intrathoracic pressure on pulmonary and systemic hemodynamics.

The Frank-Starling Law accounts for many changes in cardiac performance previously attributed to changes in contractility in that changes in contractility might have been incorrectly inferred from changing ventricular function curves (i.e. systolic performance plotted against filling pressure) if diastolic compliance also changed. To apply the Frank-Starling Law in the presence of changing diastolic compliance, it is necessary to measure end-diastolic volume directly or to calculate end-diastolic transmural pressure, which requires that pericardial pressure be known. Under most normal circumstances, increased intrathoracic pressure (and other interventions, such as vasodilators or lower-body negative pressure, that decrease central blood volume) decreases the transmural end-diastolic pressures of both ventricles, their end-diastolic volumes and stroke work. However, when ventricular interaction is significant, the effects of these interventions might be quite different; this may be important in patients with heart-failure. Although these interventions decrease RV transmural pressure, they may increase LV transmural pressure, end-diastolic volume, and thus stroke work by the Frank-Starling mechanism.

Arterial versus venous changes in vascular capacitance during nitroprusside infusion: a vascular modelling study.

The distributions of nitroprusside (NP) induced changes in vascular capacitance, arterial versus venous, are unknown. We measured canine ileal arterial and venous pressures and total (isolated loop) vascular volumes (scintigraphy), before and during NP infusion. NP sufficient to decrease perfusion pressure by 30% increased total vascular volume to 111 +/- 3% (+/- SEM) of control (p < 0.01). Increasing flow to restore perfusion pressure increased volume 4% more (p < 0.01). Assuming a two-compartment model and on the basis of the literature data, changes in venous capacitance were estimated and compared with arterial capacitance. During constant-flow perfusion, NP increased venous volume by 10.0% (vs. 18.1%, arterial). When flow was increased to restore pressure, venous volume increased by another 3.7% (vs. 2.6%, arterial). Assuming an original arterial to venous volume ratio of 133/1033, the final, constant-pressure increase in venous volume was almost 4 times the arterial increase. In conclusion, the increase in vascular volume during NP infusion was due primarily to similar-magnitude, active increases in venous and arterial capacitances (i.e., rightward shifts in pressure-volume relations). However, as venous volume is so much larger than arterial, the NP-induced increase in venous volume was greater.

The isolated working mouse heart: methodological considerations.

Our aim was to develop a working isolated murine heart model, as the extensive use of genetically engineered mice in cardiovascular research requires development of new miniaturized technology. Left ventricular (LV) function was assessed in the isolated working mouse heart perfused with recirculated oxygenated Krebs-Henseleit bicarbonate buffer (37 degrees C pH 7.4) containing 11.1 mM glucose and 0.4 mM palmitate bound to 3% albumin. The hearts worked against an afterload reservoir at a height equivalent to 50 mmHg, and heart rate was controlled by electrical pacing of the right atrium. LV pressure was measured with a micromanometer connected to a small steel cannula inserted through the apex of the heart. The experimental protocol consisted of two interventions. First, following instrumentation and stabilization, the preload reservoir was raised from a pressure equivalent of 7 to 22.5 mmHg, while pacing at 390 beats.min-1. Thereafter the height of the preload reservoir was set to 10 mmHg, and the pacing rate was varied from 260 to 600 beats.min-1. Aortic and coronary flows were measured by timed collections of effluent from the afterload line and that dripping from the heart, respectively [aortic+coronary flow=cardiac output (CO)]. Elevation of LV end-diastolic pressure (LVEDP) from approximately 5 to 10 mmHg resulted in a twofold increase in average cardiac power [product of LV developed pressure (LVDevP) and CO], whereas myocardial contractility (first derivative of LV pressure, dP/dt) and LVDevP (LV systolic pressure-LVEDP) increased only minimally (5-10%). Measured LVEDP was lower than the equivalent height of the preload reservoir by an amount that was related to the heart rate. Cardiac power, LVDevP and dP/dt were stable at heart rates up to 400 beats.min-1, but declined markedly with higher rates, consistent with the decrease in LVEDP. Thus, cardiac power was reduced to 50% of its maximum value when stimulated at approximately 500 beats.min-1, and at even higher rates there was little ejection. By systematic manipulation of the height of the preload reservoir and heart rate, we conclude that LV afterload and preload can be assessed only by high-fidelity measurement of intraventricular pressures. The heights of the afterload column and the preload reservoir are unreliable and potentially misleading indicators of LV afterload and preload.

Vascular and cardiac effects of amlodipine in acute heart failure in dogs.

BACKGROUND: Amlodipine improves exercise capacity in patients with chronic congestive heart failure (HF), but the mechanisms of this effect are unknown. OBJECTIVE: To test the hypothesis, in a canine model of acute, ischemic HF, that amlodipine increases vascular capacitance and reduces cardiac filling pressures. METHODS: Amlodipine was given to 13 anesthetized, splenectomized dogs (six controls and seven with HF). Aortic, left ventricular end-diastolic (LVEDP) and portal venous (Pportal) pressures, cardiac output, portal flow (ultrasonic probe) and intestinal blood volume (IBV, 99mTc blood-pool scintigraphy) were measured. Intestinal vascular conductance (= 1/resistance) and vascular capacitance (CAP) were measured before and 15 mins after repetitive 150 micrograms/kg dosages of amlodipine (maximum cumulative dosage, 1000 micrograms/kg). Pportal-IBV curves were obtained by impeding portal flow (pneumatic cuff), and change in CAP was defined by the change in IBV at Pportal = 7.5 mmHg. HF was induced by microsphere embolization of the left coronary artery. RESULTS: CAP increased in the control group (+ 28%, P < 0.01) but decreased (-9%, P < 0.05) in the HF group. Left ventricular stroke work increased in the control group (P < 0.05), while it decreased (P < 0.05) in the HF group, suggesting a negative inotropic effect. In the control group, LVEDP increased after amlodipine was given (P < 0.05) but did not change significantly in the HF group. CONCLUSIONS: In the acute experimental HF model, amlodipine failed to increase intestinal vascular CAP or decrease filling pressures, and may have had a negative inotropic effect. The experiment failed to demonstrate a beneficial hemodynamic effect of amlodipine in acute HF, and the mechanism of benefit of this agent in chronic HF remains unclear.