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Rationale: Cardiac myocyte–specific deletion of either glycogen synthase kinase (GSK)-3α and GSK-3β leads to cardiac protection after myocardial infarction, suggesting that deletion of both isoforms may provide synergistic protection. This is an important consideration because of the fact that all GSK-3–targeted drugs, including the drugs already in clinical trial target both isoforms of GSK-3, and none are isoform specific. Objective: To identify the consequences of combined deletion of cardiac myocyte GSK-3α and GSK-3β in heart function. Methods and Results: We generated tamoxifen-inducible cardiac myocyte–specific mice lacking both GSK-3 isoforms (double knockout). We unexpectedly found that cardiac myocyte GSK-3 is essential for cardiac homeostasis and overall survival. Serial echocardiographic analysis reveals that within 2 weeks of tamoxifen treatment, double-knockout hearts leads to excessive dilatative remodeling and ventricular dysfunction. Further experimentation with isolated adult cardiac myocytes and fibroblasts from double-knockout implicated cardiac myocytes intrinsic factors responsible for observed phenotype. Mechanistically, loss of GSK-3 in adult cardiac myocytes resulted in induction of mitotic catastrophe, a previously unreported event in cardiac myocytes. Double-knockout cardiac myocytes showed cell cycle progression resulting in increased DNA content and multinucleation. However, increased cell cycle activity was rivaled by marked activation of DNA damage, cell cycle checkpoint activation, and mitotic catastrophe–induced apoptotic cell death. Importantly, mitotic catastrophe was also confirmed in isolated adult cardiac myocytes. Conclusions: Together, our findings suggest that cardiac myocyte GSK-3 is required to maintain normal cardiac homeostasis, and its loss is incompatible with life because of cell cycle dysregulation that ultimately results in a severe fatal dilated cardiomyopathy.

Since the late 1970s when many journals published articles warning about the misuse of statistical methods in the analysis of data, researchers have become more careful about statistical analysis, but errors including low statistical power and inadequate analysis of repeated-measurement studies are still prevalent. In this review, several statistical methods are introduced that are not always familiar to basic and clinical cardiologists but may be useful for revealing the correct answer from the data. The aim of this review is not only to draw the attention of investigators to these tests but also to stress the conditions in which they are applicable. These methods are now generally available in statistical program packages. Researchers need not know how to calculate the statistics from the data but are required to select the correct method from the menu and interpret the statistical results accurately. With the choice of appropriate statistical programs, the issue is no longer how to do the test but when to do it.

Rationale: The cellular and molecular basis for post–myocardial infarction (MI) structural and functional remodeling is not well understood. Objective: Our aim was to determine if Ca 2+ influx through transient receptor potential canonical (TRPC) channels contributes to post-MI structural and functional remodeling. Methods and Results: TRPC1/3/4/6 channel mRNA increased after MI in mice and was associated with TRPC-mediated Ca 2+ entry. Cardiac myocyte–specific expression of a dominant-negative (loss-of-function) TRPC4 channel increased basal myocyte contractility and reduced hypertrophy and cardiac structural and functional remodeling after MI while increasing survival in mice. We used adenovirus-mediated expression of TRPC3/4/6 channels in cultured adult feline myocytes to define mechanistic aspects of these TRPC-related effects. TRPC3/4/6 overexpression in adult feline myocytes induced calcineurin (Cn)-nuclear factor of activated T-cells (NFAT)–mediated hypertrophic signaling, which was reliant on caveolae targeting of TRPCs. TRPC3/4/6 expression in adult feline myocytes increased rested state contractions and increased spontaneous sarcoplasmic reticulum Ca 2+ sparks mediated by enhanced phosphorylation of the ryanodine receptor. TRPC3/4/6 expression was associated with reduced contractility and response to catecholamines during steady-state pacing, likely because of enhanced sarcoplasmic reticulum Ca 2+ leak. Conclusions: Ca 2+ influx through TRPC channels expressed after MI activates pathological cardiac hypertrophy and reduces contractility reserve. Blocking post-MI TRPC activity improved post-MI cardiac structure and function.

Rationale: Autologous bone marrow- or cardiac-derived stem cell therapy for heart disease has demonstrated safety and efficacy in clinical trials but has only offered limited functional improvements. Finding the optimal stem cell type best suited for cardiac regeneration remains a key goal toward improving clinical outcomes. Objective: To determine the mechanism by which novel bone-derived stem cells support the injured heart. Methods and Results: Cortical bone stem cells (CBSCs) were isolated from EGFP+ transgenic mice and were shown to express c-kit and Sca-1 as well as 8 paracrine factors involved in cardioprotection, angiogenesis and stem cell function. Wild-type C57BL/6 mice underwent sham operation (n=21) or myocardial infarction (MI) with injection of CBSCs (n=57) or saline (n=59). Cardiac function was monitored using echocardiography with strain analysis. EGFP+ stem cells in vivo were shown to express only 2/8 factors tested (basic fibroblast growth factor and vascular endothelial growth factor) and this expression was associated with increased neovascularization of the infarct border zone. CBSC therapy improved survival, cardiac function, attenuated adverse remodeling, and decreased infarct size relative to saline-treated MI controls. By 6 weeks post-MI, EGFP+ cardiomyocytes, vascular smooth muscle cells and endothelial cells could be identified on histology. Isolated EGFP+ myocytes were smaller, more frequently mononucleated, and demonstrated fractional shortening and calcium currents indistinguishable from EGFP- myocytes from the same hearts. Conclusions: CBSCs improve survival, cardiac function, and attenuate remodeling by 1) secreting the proangiogenic factors bFGF and VEGF (stimulating endogenous neovascularization), and 2) differentiating into functional adult myocytes and vascular cells.

Rationale: Autologous bone marrow–derived or cardiac-derived stem cell therapy for heart disease has demonstrated safety and efficacy in clinical trials, but functional improvements have been limited. Finding the optimal stem cell type best suited for cardiac regeneration is the key toward improving clinical outcomes. Objective: To determine the mechanism by which novel bone-derived stem cells support the injured heart. Methods and Results: Cortical bone–derived stem cells (CBSCs) and cardiac-derived stem cells were isolated from enhanced green fluorescent protein (EGFP+) transgenic mice and were shown to express c-kit and Sca-1 as well as 8 paracrine factors involved in cardioprotection, angiogenesis, and stem cell function. Wild-type C57BL/6 mice underwent sham operation (n=21) or myocardial infarction with injection of CBSCs (n=67), cardiac-derived stem cells (n=36), or saline (n=60). Cardiac function was monitored using echocardiography. Only 2/8 paracrine factors were detected in EGFP+ CBSCs in vivo (basic fibroblast growth factor and vascular endothelial growth factor), and this expression was associated with increased neovascularization of the infarct border zone. CBSC therapy improved survival, cardiac function, regional strain, attenuated remodeling, and decreased infarct size relative to cardiac-derived stem cells– or saline-treated myocardial infarction controls. By 6 weeks, EGFP+ cardiomyocytes, vascular smooth muscle, and endothelial cells could be identified in CBSC-treated, but not in cardiac-derived stem cells–treated, animals. EGFP+ CBSC-derived isolated myocytes were smaller and more frequently mononucleated, but were functionally indistinguishable from EGFP− myocytes. Conclusions: CBSCs improve survival, cardiac function, and attenuate remodeling through the following 2 mechanisms: (1) secretion of proangiogenic factors that stimulate endogenous neovascularization, and (2) differentiation into functional adult myocytes and vascular cells.

Peptide mediators may play a role in the control of myocardial perfusion. We found immunohistochemical evidence of the peptide-degrading enzyme neutral endopeptidase (NEP) in cultured rat myocytes. Therefore, we examined the effect of an NEP inhibitor, phosphoramidon, on myocardial perfusion in rats after (1) stimulating sensory nerves with capsaicin and (2) inducing myocardial hypoperfusion with isoproterenol, with or without pretreatment with selective antagonists of the substance P (NK1) and bradykinin (B2) receptors. Three to five sequential determinations of myocardial blood flow were made in anesthetized rats by injecting 100,000 radionuclide-labeled microspheres suspended in 70% dextrose into the left ventricle. Phosphoramidon doubled coronary blood flow in response to a dose of capsaicin that was ineffective in the absence of the inhibitor. Isoproterenol (50 mg/kg IP) caused an immediate fall in blood pressure and coronary blood flow; after 20 minutes, flow had returned to normal but pressure was still subnormal. Administration of phosphoramidon reduced the recovery of blood pressure but greatly increased coronary blood flow. These changes were not altered by a substance P NK1 receptor blocker but were completely abolished by a selective bradykinin B2 receptor blocker. Our data indicate that (1) NEP is present in the rat myocardium, (2) sensory nerve-induced coronary vasodilation is markedly potentiated by NEP inhibition, (3) isoproterenol-induced myocardial hypoperfusion is prevented by NEP inhibition, and (4) this effect of NEP inhibition is due to reduced degradation of bradykinin.

We examined the ability of individual regions of the canine left ventricle to increase blood flow relative to baseline rates of perfusion. Regional coronary flow was measured by injecting radioactive microspheres over 90 seconds in seven anesthetized mongrel dogs. Preliminary experiments demonstrated a correlation between the regional distributions of blood flow during asphyxia and pharmacological vasodilatation with adenosine (mean r = 0.75; 192 regions in each of two dogs), both of which resulted in increased coronary flow. Subsequent experiments, during which coronary perfusion pressure was held constant at 80 mm Hg, examined the pattern of blood flow in 384 regions (mean weight, 106 mg) of the left ventricular free wall during resting flow and during maximal coronary flow effected by intracoronary adenosine infusion. We found that resting and maximal flow patterns were completely uncorrelated to each other in a given dog (mean r = 0.06, p = NS; n = 3 dogs). Furthermore, regional coronary reserve, defined as the ratio of maximal to resting flow, ranged from 1.75 (i.e., resting flow was 57% of maximum) to 21.9 (resting flow was 4.5% of maximum). Thus, coronary reserve is spatially heterogeneous and determined by two distinct perfusion patterns: the resting (control) pattern and the maximal perfusion pattern. Normal hearts, therefore, contain small regions that may be relatively more vulnerable to ischemia. This may explain the patchy nature of infarction with hypoxia and at reduced perfusion pressures as well as the difficulty of using global parameters to predict regional ischemia. Despite the wide dispersion of coronary reserve, we found, by autocorrelation analysis, that reserve in neighboring regions (even when separated by a distance of several tissue samples) was significantly correlated. This also applied to patterns of resting myocardial flow. Thus, both resting coronary blood flow and reserve appear to be locally continuous and may define functional zones of vascular control and vulnerability, respectively.

To determine whether coronary vasodilator reserve that persists during myocardial ischemia is present in all left ventricular regions, we measured regional blood flow in 192 left ventricular pieces (mean weight, 201 mg) in each of eight dogs by using radioactive microspheres while perfusing the left main coronary artery at 70, 50, 40, and 30 mm Hg. Flows were measured before and during adenosine infusion to determine flow reserve. Perfusion at 40 and 30 mm Hg produced ischemia in all dogs. At 70 mm Hg, 100% of left ventricular regions had significant flow reserve, compared with 92%, 55%, and 8% during perfusion at 50, 40, and 30 mm Hg, respectively. A greater amount of flow reserve and a greater number of regions responded to adenosine in the subepicardium than in the subendocardium at 50, 40, and 30 mm Hg. We conclude that coronary flow reserve persists in only a subset of left ventricular regions during ischemia and that the number of regions with persistent flow reserve decreases with perfusion pressure. These findings may best be explained by a model in which regional ischemia is a maximal coronary vasodilator and persistent pharmacological vasodilator reserve seen when global markers indicate ischemia simply reflects persistent endogenous flow reserve in myocardial regions not yet ischemic.

The coronary circulation of anesthetized dogs was tested for the presence of vascular waterfalls by manipulating coronary arterial and coronary venous pressures. The left main coronary artery and the coronary sinus were cannulated, and relationships between coronary artery pressure, coronary sinus pressure, and coronary flow were studied. Experiments were conducted during diastolic arrests, under steady state conditions, in the absence of autoregulation. Relations of coronary flow to coronary sinus pressure at constant coronary artery pressure were consistent with the presence of a vascular waterfall in the coronary sinus. When the great cardiac vein was cannulated, relations of great vein flow to great vein pressure at constant coronary artery pressure were consistent with the presence of a vascular waterfall in the great vein, indicating that waterfall behavior can occur in epicardial veins other than the coronary sinus. In dogs on right heart bypass, with the coronary sinus and great vein uncannulated, the relationship between right atrial pressure and coronary sinus pressure showed a waterfall pattern, indicating that the waterfall is not an artifact of venous cannulation. In the right heart bypass experiments, venous waterfall behavior was seen in beating hearts as well as during diastolic arrests. We conclude that a vascular waterfall is present in epicardial coronary veins which can significantly influence coronary blood flow.

The accuracy of regional myocardial blood flow measurements made with microspheres of different sizes is uncertain. Therefore, we simultaneously injected radioactive microspheres of different sizes into the left atria of dogs and sheep; the microsphere diameters were 25µ, 15µ, 9µ, 1-l0µ, and filtered 1-10µ (most > 7µ). Antipyrine was sometimes simultaneously infused for 15-60 seconds. Myocardial blood flow was altered by hemorrhage, tachycardia, supravalvar aortic constriction, or infusion of methoxamine or adenosine triphosphate; left coronary artery branches were occluded on two occasions. Sometimes the percent of untrapped microspheres was estimated. All sizes of microspheres measured similar total myocardial blood flows when the percent of untrapped microspheres was known. All indicators were distributed identically to the right and left ventricular free walls and septum; ischemic areas had a 1% excess of antipyrine. With any pair of microspheres, the larger had a subendocardial excess except for 25µ microspheres, which were in excess compared with 15µ microspheres in the higher flow layer whether it was subendocardial or subepicardial. The greatest difference for any pair of microspheres was 10.53% of flow in a layer. Antipyrine did not define which size of microspheres measured true regional blood flow, since many previously unemphasized limitations were discovered. Nevertheless, we believe that microspheres 9µ in diameter are probably the best for measuring regional myocardial blood flow.

We performed experiments on anesthetized, open-chest dogs to determine whether the pulmonary chemoreflex (bradycardia and systemic hypotension) evoked by stimulating pulmonary C-fibers also involves reflex changes in coronary vascular resistance. We perfused the circumflex coronary artery at constant pressure (usually 100 mm Hg) and recorded mean circumflex blood flow. Stimulation of pulmonary C-fibers by right atrial injection of capsaicin (10 micrograms/kg) decreased arterial blood pressure and heart rate and increased circumflex blood flow by 32-109% (P less than 0.001). Circumflex blood flow also increased, by 26-100% (P less than 0.001), when heart rate was kept constant by pacing. Coronary vasodilation was not secondary to the reflex decrease in arterial blood pressure. Injecting capsaicin (10 micrograms/kg) into the left atrium did not increase circumflex blood flow. Reflex coronary vasodilation could still be evoked when myelinated nerve fibers were blocked selectively by cooling the cervical vagus nerves to 7-8 degrees C but was abolished by cooling to 0 degrees C, by cutting the pulmonary vagal branches, or by giving atropine. Reducing coronary perfusion pressure shifted the stimulus (dose of capsaicin)-response (increase in coronary blood flow) curve to the right, but, even at low perfusion pressures, significant reflex vasodilation still occurred. Regional (transmural) distribution of myocardial blood flow was measured by the microsphere technique at various perfusion pressures. The endocardial:epicardial blood flow ratio decreased significantly as perfusion pressure was reduced, but was not altered by right atrial injection of capsaicin at any perfusion pressure. Our results indicate that stimulation of pulmonary C-fibers triggers reflex cholinergic vasodilation in all layers of the myocardium.

We investigated the effect of hypercholesterolemia on coronary and cardiac hemodynamic responses to intracoronary norepinephrine (NE) (0.01 to 10.0 micrograms/min as the bitartrate) in a Gregg cannula autoperfusion system. Coronary blood flow was measured by the radioactive microsphere technique in two groups of open-chest dogs anesthetized with pentobarbital: 10 controls and 8 that were fed a cholesterol-rich diet (CD) which doubled the serum cholesterol level. In the control dogs, NE in doses of 0.01 to 1.0 micrograms/min had no effect on coronary vascular resistance (CVR) but 10 micrograms/min caused a significant decrease to 0.58 +/- 0.12 of control. In the CD dogs, NE at doses of 1.0 and 10.0 micrograms/min significantly reduced CVR, to 0.72 +/- 0.06 and 0.52 +/- 0.11 of control, respectively. There was no consistent effect of NE, at these doses, on myocardial oxygen uptake, left ventricular stroke work index, or maximal positive dP/dt. In a second series of experiments we measured coronary flow with electromagnetic flowmeters in 11 chronically instrumented conscious dogs, 5 controls, and 6 CD. In the control dogs, intravenously administered NE hydrochloride, 0.01 microgram/min, reduced CVR to 0.74 +/- 0.07 of control, and 1.0 microgram/min increased CVR to 1.26 +/- 0.09 of control. In the CD animals, these effects were seen at a 10-fold lower NE dose, 0.001 microgram/min (0.83 +/- 0.11 of control) and 0.1 microgram/min (1.32 +/- 0.06 of control). The vasodilation was blocked by propranolol, and vasoconstriction by phentolamine. We conclude that NE at low doses activates beta-adrenoreceptors to reduce CVR and at higher doses activates alpha-adrenoreceptors to increase CVR; the vasoconstrictor response is inhibited in pentobarbital anesthetized dogs, and hypercholesterolemia sensitizes coronary vessels to both the dilator and constrictor effects of NE.

When steady state pressure-flow relations are studied in the circumflex coronary artery, pressure gradients develop between it and other branches of the left coronary artery. To assess the effects of these pressure gradients, we compared the pressure axis intercept and shape of steady state circumflex pressure-flow relations in the presence and absence of gradients after autoregulation was abolished, both in the beating heart and during long diastoles in dogs. We used peripheral coronary pressures and radionuclide-labeled microspheres to assess arterial collateral flow. In the beating heart, interarterial pressure gradients reduced the curvature at low circumflex pressures, and overestimated the mean pressure axis intercept by 7.8 mm Hg (P less than 0.05). The results were similar for the pressure-flow relations derived during long diastoles. This overestimation exaggerates the difference between the pressure axis intercept and coronary sinus pressure. The peripheral coronary pressure and microsphere results indicate that these effects are mediated largely by arterial collateral flow.

Total and regional coronary blood flow were measured in dogs by left atrial injection of carbonized microspheres labeled with different radioactive isotopes (mean diameter 14 to 61µ). Simultaneously blood was collected at 20 ml/min from a catheter tied into a peripheral artery. The ratios of flow to radioactivity in myocardium and arterial blood should be equal if microspheres are well mixed in the aortic root and are distributed regionally in proportion to flow. This was proved in seven right heart by-pass experiments where coronary venous drainage was measured directly. Also, less than 0.1% of total myocardial radioactivity appeared in coronary venous blood, even with hypoxemia and small microspheres. Total coronary flow in seven conscious dogs averaged 95 to 150 ml/min/100 g heart; and flow to the left ventricle was 111 to 169 ml/100 g. Although not validated independently, there was evidence that values for flow to each ventricle, the atria and the septum were correct. The radioactivity per gram of left ventricular subendocardial muscle was 2.5 times that of subepicardial muscle using microspheres 51 to 61µ in diameter, but the ratios were 1.4 and 1.3 using microspheres of mean diameters 20 to 23µ and 14µ, respectively. It is unlikely that any of these microspheres measure blood flow to small portions of the ventricle.

Chronically hypertrophied right ventricles function normally under high systolic pressures, whereas normal right ventricles fail when they are acutely subjected to similar pressures. This phenomenon may be partly due to adaptation of the coronary circulation as well as to hypertrophy. Knowledge of the magnitude and distribution of coronary blood flow and the degree of coronary vascular reserve are important in understanding the function of hypertrophied myocardium. We studied these variables in 16 awake, 5-12-week-old, tranquilized lambs; 9 of the lambs had had their main pulmonary artery banded at 2 days of age. Pressures, cardiac output, and coronary blood flow (radioactive microsphere method) were measured at rest and during two stress states--isoproterenol and dextran infusion. Ventricular function was similar in control and banded lambs. We found significant right ventricular hypertension and both right ventricular and septal hypertrophy in the banded lambs. Total coronary blood flow per gram was slightly higher in banded lambs in all states, and right ventricular flow per gram was significantly elevated at rest and during isoproterenol infusion. Right ventricular coronary resistance per gram was significantly lower in banded lambs in all states. These changes demonstrate that hypertrophied right ventricular tissue is not ischemic at rest, since there is vascular reserve. The changes also raise the question of increased vascularity in hypertrophied myocardium. Right ventricular oxygen supply per unit oxygen demand was increased in banded lambs at rest and during isoproterenol infusion. This finding suggests that hypertrophied myocardium has inefficient oxygen utilization, low oxygen extraction, or both.

The shape of the coronary arterial pressure-flow relationship results from the interaction of a number of poorly understood physiological factors. Experiments in which coronary inflow and outflow pressures were coupled so that driving pressure was held constant showed that changes in inflow or outflow pressures altered coronary blood flow: coronary vascular resistance varied inversely with changes inflow pressure below 50 mm Hg and with changes in outflow pressure below 80 mm Hg. The magnitude of the influence of inflow pressure on resistance also depended on the fixed level of outflow pressure, the influence being large when the outflow pressure was low, and small when it was high. Inflow and outflow pressures, then, are two physiological factors which are determinants of the shape of the pressure-flow relationship, and their interaction contributes to the degree of curvature found in a particular relationship. These findings suggest that the use of linear regression in the interpretation of pressure-flow relationships results in poor estimation of resistance and zero-flow pressure. Other experiments measuring regional coronary blood flow using radionuclide-labeled microspheres resulted in the same inverse relationship between inflow pressure and resistance, regardless of mural depth, indicating that inflow pressure may influence resistance by distending vessels, rather than by causing sequential cessation of perfusion in successive transmural layers.

To determine whether left ventricular hypertrophy [LVH] altered total and regional coronary blood flow, we inflated a balloon around the ascending aorta of nine dogs; six acute and six sham-operated dogs were controls. After 6 weeks, all dogs were studied with an open chest under anesthesia; the balloons were deflated. There was moderate LVH as shown by increased left ventricular weight and fiber diameter. At rest there were no major differences of coronary flow or resistance per gram of muscle. With maximal coronary vasodilation due to adenosine or carbochrome, mean coronary vascular resistance was 84% higher in LVH than in normal hearts; with isoproterenol, resistance was 54% higher in LVH. These changes were similar in right and left ventricles. Minimal coronary resistance at end diastole also was higher in LVH--64% and 94% for the two sets of vasodilators, respectively. There were no significant differences in capillary or large vessel proportional volumes in LVH and control dogs, but arterial capacity could not be estimated. The raised minimal coronary resistance suggests the possibility that, with stress, coronary flow, especially to subendocardial muscle, might be inappropriate and perhaps cause ischemic damage. However, the changes noted might have been due to coronary arterial responses to raised coronary pressures rather than to hypertrophy itself.

distribution of left ventricular blood flow in anesthetized dogs The role of autoregulation and tissue diastolic pressures in the transmural 1524-4571 Copyright © 1979 American Heart Association. All rights reserved. Print ISSN: 0009-7330. Online ISSN: TX 72514 Circulation Research is published by the American Heart Association. 7272 Greenville Avenue, Dallas, 1979, 45:804-815 Circulation Research http://circres.ahajournals.org/content/45/6/804.citation located on the World Wide Web at: The online version of this article, along with updated information and services, is

SUMMARY Decreased cardiac output, coronary blood flow, and systemic oxygen transport in polycythemia are attributed to increased blood viscosity and regarded as potentially harmful. We studied the effects of isovolemic polycythemia on these variables as well as on myocardial oxygen consumption and regional myocardial blood flow in 31 anesthetized dogs, seven with cannulated left main coronary arteries. Measurements were made at rest, during hypoxemia or adenosine infusions, and with aortic stenosis, pacing, or an aorto-atrial fistula. When hematocrit increased from 42% to 66%, it reduced cardiac output by 36% and systemic oxygen transport by 8%; with hypoxemia, cardiac output rose in polycythemic dogs. Normoxemic polycythemia decreased myocardial blood flow by 46% and increased mean coronary resistance by 54%, slightly decreased myocardial oxygen transport and consumption, and did not alter coronary sinus oxygen tension or myocardial oxygen extraction. Cardiac stress, hypoxemia, and adenosine infusion lowered coronary resistance in polycythemic dogs. Left ventricular myocardial oxygen transport was dependent on pressure work and not on arterial oxygen content or hematocrit. With maximal coronary vasodilation, coronary vascular resistance at hematocrits of 66% was 1.5 times that at 42%. Polycythemia per se did not alter the even distribution of flows across the left ventricular wall, but subendocardial underperfusion began at higher perfusion pressures in polycythemic than in normocythemic dogs. We conclude that autoregulation plays a role in regulating flows and oxygen transport in polycythemia. With maximal coronary vasodilation, however, the increased viscosity of polycythemic blood could be an important factor reducing the amount of myocardial blood flow and oxygen transport. THE EFFECTS of polycythemia on the circulation depend in part on whether there is an associated increase in blood volume 1 which is usually elevated in most forms of polycythemia in man. 2 " 5 Because of the raised blood volume, cardiac output is usually increased, unless there is heart failure. Systemic oxygen transport (cardiac output times arterial oxygen content) is therefore increased above normal when arterial oxygen saturation is normal 4 and may be normal or only moderately reduced when

In 7 conscious dogs, left ventricular diastolic volume (V) was estimated by taking biplane cineradiographs with the left ventricular cavity previously outlined by permanent radiopaque markers. Left ventricular pressure (P) was measured with an implanted miniature transducer. There were two rapid filling periods during early and late diastole; little filling occurred during the middle third of diastole (diastasis). The diastolic pressure-volume relationship was approximately exponential and was fitted by the equation P=- a+be c v , where, a, b , and c are positive constants; the relationship appeared to be determined principally by the elastic properties. The effects of infusions of saline, isoproterenol, calcium gluconate, and methoxamine suggested that viscous and inertial properties are also important determinants of diastolic left ventricular mechanics. No significant series viscosity was observed. Plastic properties were not detected. The elastic properties were not affected by agents having a positive inotropic effect. End-diastolic pressure often differed from that predicted by the exponential equation above, suggesting that it is not a reliable index of enddiastolic volume and left ventricular compliance.

Subendocardial ischemia without anatomic coronary artery obstruction may result from a discrepancy between metabolic needs and available blood supply. We studied this in open-chest anesthetized dogs and measured pressures in aorta and left ventricle (LV), phasic left coronary arterial blood flow (CBF) by electromagnetic flowmeter, total CBF and LV subendocardial (endo) and subepicardial (epi) flow with radioactive microspheres 8-10µ, in diameter. Since LV Subendocardial flow is mainly or entirely diastolic, it should depend on coronary driving pressure and duration of diastole (i.e., the area between aortic and left ventricular diastolic pressures). This diastolic pressure time index (DPTI) was varied by opening arteriovenous fistulas to lower aortic diastolic pressure, constricting the ascending aorta to raise LV diastolic pressure and pacing to shorten diastole. Myocardial oxygen needs were estimated from the tension time index (TTI). Normal endo-epi flow ratios per gram (1:1) fell to 0.1:1 with these procedures and paralleled a fall in diastolic flow fraction (often nearly zero) and postischemic coronary reactive hyperemic responses. These changes occurred despite normal or raised mean CBF and 300-500% increase in systolic CBF. The altered flow ratios were best predicted by relating them to the ratio of DPTI (supply) to TTI (demand).

We have investigated the effects of sudden changes in the load against which the left ventricle contracts in healthy conscious dogs. During a steady state, initial responses were assessed by comparing the beat before with the beat after such a change. Flow was measured by electromagnetic flowmeters and pressure usually by a catheter-tip transducer. Results show that under the conditions of these experiments the curves relating external work and power to load are consistent with the parabolic relationship shown for isolated hearts and muscle strips and that in each case the left ventricle normally functions near the peak of the curve. When an increased load was maintained until a new steady state was reached the left ventricle still functioned on the descending limbs of what presumably were different work-load and power-load curves. It was concluded from this that either the increase in load was too great or the time too short for reflex humoral and intrinsic mechanisms to readjust and permit the ventricle to function again at the peak of each curve, or that the circulatory system does not make relatively rapid adaptations in this way to an increase in systemic load. The immediate effects of changes in load on left ventricular stroke volume were similar to those seen in isolated preparations. Stroke volume varied inversely with the load. Stroke volume changes were accompanied by changes in the duration, rate, and velocity of ejection. The duration of the isovolumetric phase was affected little but the period from valve closure to the end of ventricular relaxation varied with the load so that the total duration of contraction and relaxation of the ventricle was relatively unchanged, though an increase in load did tend to prolong it. Before the onset of the baroreceptor response the right ventricle was not affected, the two ventricles acting independently in relation to all these changes.