Total, phasic, and regional myocardial blood flow in aortic stenosis.

The effect of aortic stenosis on total, phasic, and regional myocardial flow was studied in 16 anesthetized, open-chested dogs. An adjustable catheter device was used to produce increasing aortic obstruction, the severity of which was judged from the left ventricular aortic peak systolic gradient as mild (< 25 mm. Hg), moderate (26 to 50 mm. Hg) and severe (> 50 mm. Hg). The supply/demand index was estimated from the ratio of diastolic pressure time index to systolic pressure time index ($\text{DPTI}\text{SPTI}$). The ratio of diastolic to systolic coronary blood flow ($\text{DIAS}\text{SYS}$) was determined from the flow tracings. Total myocardial flow and endocardial/epicardial flow ratios ($\text{ENDO}\text{EPI}$) were determined by injecting four differently-labeled 7 to 9 micron microspheres in the left atrium during control, mild, moderate, and severe aortic stenosis.The supply/demand ($\text{DPTI}\text{SPTI}$) index decreased significantly at all levels of aortic stenosis because of a decrease in DPTI and an increase in SPTI. The $\text{DIAS}\text{SYS}$ coronary flow ratio and the $\text{ENDO}\text{EPI}$ myocardial flow ratio were not significantly changed during aortic stenosis. The total myocardial flow was significantly higher than control only during severe aortic stenosis.The results indicate that, for all degrees of experimental aortic stenosis, there were significant decreases in $\text{DPTI}\text{SPTI}$ but no significant changes in $\text{DIAS}\text{SYS}$ coronary flow ratio or the distribution of myocardial perfusion. Thus, in acute, experimental aortic stenosis, there is evidence of increased myocardial oxygen demand, but endocardial perfusion is not changed significantly.     

Coronary sinus blood flow at rest and during isometric exercise in patients with aortic valve disease: Mechanism of angina pectoris in presence of normal coronary arteries

In 46 patients with aortic valve disease, coronary sinus blood flow was measured using a continuous thermodilution method both at rest and during isometric handgrip excercise. All patients had normal coronary angiograms. The patients were separated into three groups: Group I, 12 patients with aortic stenosis (systolic gradient 72 ± 12 mm Hg); Group II, 15 patients with both aortic stenosis and regurgitation; Group III, 19 patients with aortic regurgitation. At rest, the coronary sinus blood flow was two to three times normal. However, when corrected for left ventricular mass (ml/100 g), flow was within normal limits. The ratio diastolic pressure-time index/systolic pressure-time index ($\text{DPTI}\text{SPTI}$) was decreased in all three groups at rest. During isometric exercise, coronary sinus blood flow increased significantly: by 60 percent in Group I, by 88 percent in Group II and by 118 percent in Group III. There was a significant reduction of the $\text{DPTI}\text{SPTI}$ ratio.Of the 18 patients with angina on effort during the test, 7 were in Group I, 6 in Group II and 5 in Group III. There were no differences in the coronary sinus blood flow between the patients with angina and those who were pain-free, either at rest or during exercise. Angina pectoris does not appear to be caused by a failure of coronary blood flow to increase. There was no discrepancy between myocardial demand, as measured by the pressure-time index and coronary blood flow. However, the $\text{DPTI}\text{SPTI}$ ratio was significantly lower during exercise in the patients with angina than in those who were pain-free. Underperfusion of the subendocardial muscle seems to be a causative factor in the patients with angina.     

Physiologic responses to epinephrine infusion: The basis for a new stress test for coronary artery disease

Since many patients with chest pain cannot exercise adequately, an alternative stress would be useful to evaluate coronary reserve. We studied the physiologic responses to epinephrine to assess its potential. We report on 39 patients with chest pain. Doses from 0.03 to 0.30 μg/kg/min were administered intravenously. Heart rate increased from 72 ± 10 to 86 ± 12 bpm (mean ± SD), systolic blood pressure (BP) from 122 ± 20 to 158 ± 18 mm Hg (increased afterload), and rate-pressure product/100 from 88 ± 21 to 133 ± 18. Rate-corrected pre-ejection period decreased from 141 ± 23 to 92 ± 14 msec and $\text{LVET}\text{PEP}$ ratio from 0.41 ± 0.1 to 0.24 ± 0.05 (increased contractility). Increased afterload and contractility increased myocardial oxygen demand. Simultaneously diastolic time and BP decreased, reducing myocardial blood supply. The endocardial viability ratio fell from 1.27 ± 0.3 to 0.80 ± 0.2. These data suggest that epinephrine infusion would be a useful stress test for coronary disease and are supported by a sensitivity of 87% and specificity of 100% in 23 patients with known coronary anatomy.     

Cardioadrenergic factor in essential hypertension

Determination of STI in 54 untreated essential hypertensive subjects and 17 normal subjects revealed marked differences among three groups of patients. Those with borderline hypertension (29) had a short PEP and IVC periods (93 ± 2.1 and 28 ± 0.7 msec., respectively, p < 0.001) (mean ± S.E.) reduced $\text{PEP}\text{LVET}$ (0.323 ± 0.009, p < 0.05) and increased $\text{DP}\text{IVC}$ (3,484 ± 257 mm. Hg per second, p < 0.001). Among those with established hypertension, two groups of equal age and diastolic pressure were identified: nine with marked variations in blood pressure and a hyperkinetic heart clinically and 16 with fixed hypertension; none had cardiac or renal decompensation. Those with a hyperkinetic circulation had normal PEP, IVC, and $\text{PEP}\text{LVET}$ despite a high diastolic pressure (122 ± 7.1 mm. Hg); $\text{DP}\text{IVC}$ was elevated (3,651 ± 497 mm. Hg per second, p < 0.001) as in those with borderline hypertension. In contrast, the patients with fixed hypertension had longer PEP and IVC (p < 0.001), higher $\text{PEP}\text{LVET}$ (p < 0.001), and normal $\text{DP}\text{IVC}$. Propranolol (10 mg. intravenously) slowed heart rate and prolonged PEP and IVC more in patients with a hyperkinetic circulation and in those with borderline hypertension than in those with fixed hypertension.These results suggest the presence of an increased cardioadrenergic drive not only in borderline hypertension, but also in a subgroup of patients with established hypertension. Left ventricular hypertrophy (ECG) was found in 1 out of 9 patients with hyperkinetic heart but in 6 out of 16 with fixed hypertension; cardiac index was high normal in the first group but reduced in the latter (3.32 vs 2.38 L./min./M.², p < 0.001). This factor as determined by the systolic time interval might, therefore, be important in determining cardiac prognosis or planning therapy.     

Left ventricular function in systole and diastole in constrictive pericarditis

Left ventricular function was studied in systole and diastole in 30 patients with constrictive pericarditis. Left ventricular end-diastolic volume was used to divide the patients into three arbitrary groups: severe constriction (EDV < 25 ml./M.²), moderate constriction (EDV 25 to 50 ml./M.²), and mild constriction (EDV > 50 ml./M.²).The patients had high ventricular diastolic and venous filling pressures (mean LVEDP = 23 ± 7 mm. Hg, mean RVEDP = 20 ± 7 mm. Hg). Measurements related to absolute fiber shortening (stroke index, stroke work index, and left ventricular ejection rate) were reduced and linearly related to the degree of constriction as assessed by the end-diastolic volume.Measurements of relative fiber shortening or lengthening (ejection and filling fraction and circumferential fiber shortening) were normal despite great reduction in ventricular volumes.Velocity measurements, peak LV $\text{dp}\text{dt}$ and mean velocity of circumferential fiber shortening were normal or slightly reduced.These changes were reflected in the systolic time interval measurements pre-ejection phase, left ventricular ejection time, and the ratio $\text{PEP}\text{LVET}$.Diastolic function of the ventricle was abnormal; the distensibility index of the ventriculo-pericardial system ($\text{ΔV}\text{ΔP}$) was low and the passive elastic modulus in-increased. The change in compliance correlated with the degree of constriction and there was a linear relationship between compliance and EDV.The ventricle was underloaded despite the high filling pressure and stroke work index was reduced; extrinsic compression raised the diastolic pressure and reduced left ventricular volumes.     

Hemodynamic effects of continuous abdominal binding during cardiac arrest and resuscitation

Abdominal binding improves arterial pressure and flow during cardiopulmonary resuscitation (CPR). This study was undertaken to assess the mechanisms of improved hemodynamics during cardiac arrest and CPR with continuous abdominal binding in a canine model (n = 8). Carotid and inferior vena caval (IVC) flow probes and cineangiography were used to observe magnitude and direction of blood flow. CPR with binding significantly increased (p < 0.001) systolic aortic (Ao) (49 ± 11 vs 34± 12mm Hg), right atrial (RA) (49 ± 11 vs 31 ± 10 mm Hg) and IVC pressure (50 ± 7 versus 31 ± 11 mm Hg) and common carotid flow (1.1 ± 0.4 vs 0.7 ± 0.4 ml/min/kg, p < 0.05) compared with CPR without binding. Aortic, RA and IVC diastolic pressures increased similarly. Binding decreased the diastolic Ao-IVC pressure difference by 8 ± 12 mm Hg and decreased net IVC flow (0.5 ± 1.4 vs 1.4 ± 1.2 ml/min/kg, p < 0.05). Binding also decreased coronary perfusion pressure (Ao-RA) in 5 of 8 dogs. Cineangiograms showed tricuspid incompetence and reflux from the right atrium to the inferior vena cava during chest compression and IVC-to-right heart inflow during relaxation, which was confirmed by the flowmeter data. Abdominal binding during CPR decreased the size of the perfused vascular bed by inhibiting subdiaphragmatic flow and increased intrathoracic pressure for a given chest compression force, leading to preferential cephalad flow. However, coronary perfusion pressure was often adversely affected. Further studies should be undertaken before the widespread clinical application of continuous abdominal binding during CPR.     

Pre- and postoperative hemodynamic and cineangiocardiographic assessment of left ventricular function in patients with aortic regurgitation.

Hemodynamic and angiocardiographic analysis was performed prior to and 14 months on the average following valve replacement in 11 patients with severe, isolated, pure, chronic aortic regurgitation.The aortic diastolic pressure, reduced prior to surgery, reverted to normal as did the cardiac index. Left ventricular filling pressure, elevated prior to surgery, returned to normal while aortic systolic pressure did not vary substantially. The markedly increased stroke volume returned to normal as did the net left ventricular stroke work. Left ventricular end-diastolic and end-systolic volumes, also markedly elevated, decreased but did not return to normal levels.The shape of the left ventricle, which was more spherical than normal during end-systole prior to surgery, as evidenced by the decrease in the systolic axis ratio, reverted to normal.The ejection fraction, severely reduced before surgery, increased moderately (46 ± 13 vs 51 ± 19 per cent) as did the extent of circumferential fiber shortening (δD) (21 ± 8 vs 27 ± 12 per cent). The mean velocity of fiber shortening ($\text{VCF}$) increased significantly (0.68 ± 0.2 vs 1.03 ± 0.47 circ./sec.), as did the mean left ventricular ejection rate (1.32 ± 0.48 vs 1.91 ± 0.76).Comparative analysis of the evolution of left ventricular function indices and of extramyocardial factors (end-diastolic fiber stretching and impedance to ejection) showed that whereas in some cases myocardial damage appeared to be irreversible, in others dramatic improvement sometimes occurred following surgery. It was not possible, however, to determine the threshold below which the damage was irreversible.It may therefore be concluded that in some patients with severe regurgitation attended by profound myocardial insufficiency, correction of the valvular defect could produce not only clinical and hemodynamic improvement, but also improvement in myocardial contractile status.     

Effect of the undisturbed pericardium on left ventricular size and performance during acute volume loading

Studies in instrumented dogs have suggested that the pericardium alters left ventricular diastolic pressure-volume relations and thus may influence systolic performance. However, the instrumentation used in these studies disrupts the pericardium and may have influenced the results. We therefore studied five conscious dogs by methods not traumatic to the pericardium, before and after pericardiectomy. Although heart rate and left ventricular systolic and end-diastolic pressures were not different before or after pericardiectomy, either at rest or during volume loading, end-diastolic volume measured by biplane two-dimensional echocardiography increased post pericardiectomy at rest from 38 ± 4 (SE) to 61 ± 4 ml (p < 0.05) and during volume loading from 68 ± 5 to 79 ± 5 ml (p < 0.005). After pericardiectomy, ejection fraction was unchanged, but the peak value of the first derivative of left ventricular systolic pressure ($\text{dP}\text{dt}$) increased significantly at rest from 17 ± 2 to 26 ± 4.0 × 10² mm Hg/sec. We conclude that pericardiectomy shifts the left ventricular end-diastolic pressure-volume curve to the right and increases the systolic isovolumic index of $\text{dP}\text{dt}$ in the basal state.     

Acute effects of ethanol on myocardial blood flow in the nonischemic and ischemic heart

To determine the effects of ethanol on myocardial blood flow in the non-ischemic and ischemic heart, coronary blood flow was measured with radionuclide-tagged microspheres in the anesthetized dog before and after intravenous administration of 1.7 g/kg body weight of ethanol. In non-ischemic dogs, at an average peak blood ethanol level of 225 ± 8 mg/dl (mean ± standard error of the mean), left atrial pressure increased from 5.7 ± 0.6 to 7.7 ± 0.8 mm Hg (p <0.01) and heart rate slowed from 179 ± 8 to 171 ± 8 min^?1 (p <0.001) but mean aortic pressure and cardiac output were unchanged. Average myocardial blood flow increased from 122 ± 5 to 143 ± 8 ml/min per 100 g (p <0.001). In dogs given ethanol after coronary occlusion, at an average peak blood ethanol level of 201 ± 13 mg/dl, left atrlal pressure increased from 6.3 ± 0.6 to 7.4 ± 1.4 mm Hg (p <0.05) but there was no significant change in heart rate, mean aortic pressure or peak positive first derivative of left ventricular pressure ($\text{dP}\text{dt}$). In these dogs, there was a significant change (F = 6.47, p <0.001) in the distribution of myocardial blood flow. In the nonischemic zone, blood flow increased from 118 ± 7 to 148 ± 14 ml/min per 100 g (p <0.005), whereas in the ischemie zone it declined from 30 ± 6 to 20 ± 5 ml/min per 100 g (p <0.02). Myocardial tissue demonstrating myocardial perfusion equal to or greater than 80 percent of preligation levels showed a significant increment of blood flow after ethanol; by contrast, myocardial tissue having blood flow levels equal to or less than 60 percent of preligation levels showed a significant decline in blood flow.Thus, ethanol increases coronary blood flow in the nonischemic myocardium. However, in the acutely ischemic heart, ethanol produces an unfavorable redistribution of myocardial blood flow with flow in the non-ischemic myocardium increasing, at least in part, at the expense of blood flow to ischemic myocardium, producing in effect a “coronary steal.”     

Effect of arterial pressure on left ventricular O2 consumption,coronary blood flow,and reserve capacity following coronary occlusion

The effect of mean systemic arterial pressure $\text{(}\text{SAP}\text{)}$ on myocardial O₂ consumption (MV?O₂) coronary blood flow (CBF) and the reduction of left ventricular (LV) reserve capacity resulting from coronary artery occlusion was studied in 25 open-chest pentobarbital anesthetized dogs with fixed cardiac output and controlled heart rate (HR) and $\text{SAP}$. In all animals, baseline MV?O₂ and CBF were obtained and LV reserve capacity was determined by identifying the HR and $\text{SAP}$ level which raised mean left atrial pressure to 12 mm. Hg. After uniform placement of a pericoronary snare, the dogs were randomized to five equal groups, and $\text{SAP}$ was set at 40, 70 (two groups), 100, and 130 mm. Hg. MV?O₂ and CBF were redetermined and the coronary artery was ligated in all except one group (70 mm. Hg) which served as sham control. Thirty minutes after coronary occlusion, MV?O₂, CBF, and LV reserve capacity were determined again. Percent of nonperfused myocardium did not differ among groups (27.6 ± 1%). MV?O₂ bore a linear relationship to $\text{SAP}$ setting whereas CBF bore a curvilinear relationship. Coronary occlusion did not modify these relationships. Significant, but similar decreases in tolerated HR (23.1 ± 4.7 min.^?1) and $\text{SAP}$ (41.9 ± 6.2 mm. Hg) from control values were observed in all four groups regardless of $\text{SAP}$ setting.We concluded that the impact of coronary ligation on MV?O₂, CBF, the loss of functional reserve capacity, and possibly the extent of ischemic injury of the left ventricle, is not modified by afterload changes. However, optimal O₂ supply-to-demand ratio appears at $\text{SAP}$ of about 100 mm. Hg.     

Effects of acute right ventricular systolic hypertension on regional myocardial blood flow in anesthetized dogs

An important determinant of right ventricular (RV) myocardial blood flow is coronary driving pressure (CDP)—the pressure difference between RV and aorta. Since right ventricular systolic hypertension (RVSH) decreases RV CDP, it might limit blood flow to RV muscle. To study this we constricted the pulmonary artery in openchest dogs to give RV to aortic systolic pressure ratios of 0.25 to 0.40 (mild RVSH) and over 0.40 (moderate RVSH). We measured regional myocardial blood flow with 8 to 10 μ diameter radioactive microspheres, RV CDP by integrating the aortic-RV pressure difference per minute (pressure index—PI), and assessed myocardial oxygen needs of each ventricle from its tensiontime index (TTI).Flow to RV wall rose with mild and fell with moderate RVSH; differences were not significant. The ratio of RV myocardial flow to TTI remained normal with mild RVSH but fell 50 per cent with moderate RVSH. The ratio of RV PI to TTI was 10.3 ± 2.7 (mean and standard deviation) in controls, 5.6 ± 1.4 in mild RVSH, 2.4 ± 1.0 in moderate RVSH, and 1.8 ± 0.6 with acute heart failure.Reducing RV PI initially causes coronary vasodilatation. After maximal vasodilatation, further reduction decreases flow relative to oxygen needs. Underperfusion of RV myocardium may be predicted from information derived from RV and aortic pressure tracings.     

Antihypertensive effect of cardiovascular Ca2+-antagonist in hypertensive patients in the absence and presence of beta-adrenergic blockade

The effect of the administration of a cardiovascular Ca²⁺-antagonist (nifedipine) on arterial blood pressure, heart rate, and plasma renin activity was investigated.Blood pressure of normotensive healthy volunteers (n = 4) does not change significantly by administration of 10 mg. (from $\text{119}\text{78}\text{to}\text{120}\text{75}\text{mm. Hg}$) and 30 mg. (from $\text{114}\text{69}\text{to}\text{105}\text{66}\text{mm. Hg}$) of nifedipine. When nifedipine (30 mg.) is administered with propranolol (beta-blockade), a slight decrease of systolic and diastolic blood pressure was observed (from $\text{119}\text{73}\text{to}\text{104}\text{67}\text{mm. Hg}$). Blood pressure of hypertensive patients is significantly lowered by 10 mg. of nifedipine from 172.9 to 130.3 mm. Hg (25 per cent reduction) systolic, and from 112.9 to 86.6 mm. Hg (23 per cent) diastolic (n = 7). Thirty mg. nifedipine had a slightly stronger hypotensive effect, namely 27 per cent reduction in systolic and 28 per cent in diastolic values (n = 9). Combined administration of nifedipine and propranolol, resulted in lowering initial blood pressure by 32 per cent and 30 per cent reduction in systolic and diastolic (n = 8), respectively.The heart rate of normotensive patients hardly changes with administration of 10 and 30 mg. of nifedipine and combined medication. But in hypertensive subjects it is significantly increased by nifedipine; from 66.3 to 80.3 (p < 0.001) by 10 mg., and from 70.0 to 82.2 beats/minute (p < 0.01) by 30 mg. On the contrary, combined administration of nifedipine and propranolol causes no increase or only a slight decrease in heart rate (from 68 to 66 beats/minute).Plasma renin activity of normotensive and hypertensive subjects is increased by 30 mg. of nifedipine. Combined administration of nifedipine and propranolol decreases plasma renin activity in both normotensive and hypertensive patients.The antihypertensive effect of nifedipine is enhanced and prolonged by propranolol. The observed increase in heart rate and plasma renin activity with nifedipine is inhibited by propranolol, probably by inhibiting the cardiovascular effects of the activity of the sympathetic nervous system.The results of this study indicate that oral administration of nifedipine is very effective in lowering arterial blood pressure in hypertensive patients, especially when combined with propranolol.Administration of nifedipine with beta-blockade resulted in satisfactory management of hypertension with minimal adverse drug reactions which could be possibly attributed to the preparation, especially in the management of hypertensive emergencies including hypertension associated with acute myocardial infarction and coronary insufficiency.     

Ventricular function and coronary hemodynamics after intravenous nitroglycerin in coronary artery disease.

Left ventricular dynamics as well as systemic and coronary hemodynamics were determined in 14 patients with coronary artery disease (1) under control conditions, (2) under intravenous infusion of nitroglycerin, (3) under continued infusion of nitroglycerin with restored arterial and pulmonary artery pressures induced by the parallel infusion of dextran. Heart rate was kept constant by atrial pacing.Intravenous nitroglycerin infusion resulted in a significant reduction in left ventricular systolic (20 per cent) and end-diastolic pressure (43 per cent), peak $\text{dp}\text{dt}$ (13 per cent), cardiac index (16 per cent), stroke volume index (15 per cent), and stroke work index (30 per cent). Peak (dp/dt/total pressure) increased (15 per cent). Pulmonary vascular resistance markedly decreased (29 per cent), whereas total peripheral resistance did not change significantly (?3 per cent). Both coronary blood flow of the left ventricle (13 per cent) and myocardial oxygen consumption (15 per cent) decreased parallel to the reduction in preload and afterload. The action of nitroglycerin at restored left ventricular and pulmonary artery pressures was characterized by increase in peak $\text{dp}\text{dt}$ (12 per cent), peak ($\text{dp}\text{dt}$ total pressure) (18 per cent), cardiac index (13 per cent), stroke volume index (14 per cent), and stroke work index (10 per cent). Both coronary blood flow (28 per cent) and myocardial oxygen consumption (21 per cent) increased parallel to the enhancement of ventricular performance.The results demonstrate that intravenous nitroglycerin produces effective diastolic and systolic unloading of the heart associated with reduction in myocardial oxygen consumption and in coronary blood flow. There was marked vascular pooling which quantitatively averaged 437 ± 128 ml. This occurred concomitant with a 43 per cent decrease in left ventricular end-diastolic pressure or a 20 per cent decrease in peak systolic pressure. Significant coronary dilating properties of nitroglycerin could not be detected in these coronary patients. The increase in left ventricular contractility indices at restored pressure suggests a moderate but significant positive inotropic effect of nitroglycerin.     

Blood flow cessation at external pressure in the skin of normal human limbs. Photoelectric recordings compared to isotope washout and to local intraarterial blood pressure.

This paper is devoted to elucidating the questions: (a) Can cessation of skin blood flow caused by external counterpressure be recorded photoelectrically? and (b) What relation exists between the external counterpressure required for cessation of skin blood flow and the local intraarterial blood pressure in normal human limbs? Skin blanching by external counterpressure was recorded photoelectrically and the blanching threshold external pressure (BTEP) was compared to the skin blood flow cessation external pressure (FCEP) determined as the minimal external pressure required to stop the washout from an intracutaneous depot of [¹³¹I⁻]iodine mixed with histamine. The external pressure was measured by air-filled plastic cushions and the local intraarterial blood pressure was measured by isovolumetric manometers with microcannulas. At the ankle in 13 normal subjects, the BTEP averaged 84.3 mm Hg (SD, 8.9) and the FCEP averaged 80.3 mm Hg (SD, 9.0) (P < 0.10). The SD_Diff. was 5.5 mm Hg. The intraarterial blood pressure in the posterior tibial artery averaged $\text{154}\text{72}\text{mm Hg}$ (mean arterial blood pressure, 93 mm Hg). The BTEP was also measured on the heel and on the arm: on average, 71.1 (SD, 12.5) and 70.8 mm Hg (SD, 7.2). The intraarterial blood pressure in the brachial artery averaged $\text{128}\text{71}\text{mm Hg}$ (mean arterial blood pressure, 95 mm Hg). The data show that cessation of skin blood flow can be estimated by photoelectric techniques and that the required external pressure is close to or slightly above the intraarterial diastolic blood pressure. The clinical application of BTEP is discussed.     

Effect of norepinephrine on coronary hemodynamics in coronary stenotic canine model

The effect of intracoronary injection of 1μ norepinephrine was assessed in 14 open-chest dogs anesthetized with alpha chloralose. Studies were performed before and after partial coronary artery constriction by a circumferential snare. Aortic pressure, coronary pressure distal to the stenosis, and coronary flow were monitored before and after injection of norepinephrine. Calculated values were stenotic resistance and distal coronary resistance. Before coronary constriction, norepinephrine resulted in an early minimal increase in coronary flow and decrease in distal coronary resistance with prompt return to control values. In contrast with high grade coronary constriction, at 15 seconds after norepinephrine coronary flow decreased (29.8 ± 3.4 to 22.9 ± 3.6 ml./minute) (p < 0.05), coronary pressure decreased (58.8 ± 1.3 to 28.8 ± 2.6 mm. Hg) (p < 0.05), and stenotic resistance increased (2.04 ± 0.26 to 4.25 ± 2.66 mm. Hg/ml. min.^?1) (p < 0.05) without change in heart rate or aortic pressure. These changes persisted over a two minute period of observation following norepinephrine. In the stenotic model the decrease in coronary pressure and coronary flow and increase in stenotic resistance were blocked by pretreatment with propranolol but not by phenoxybenzamine. Administration of isoproterenol resulted in changes similar to those induced by norepinephrine in the stenotic model. Simulation of alteration of peripheral resistance in an in vitro model demonstrated that with a high initial stenotic resistance, a decrease in peripheral resistance resulted in an increase in stenotic resistance. We conclude that the decrease in coronary pressure following norepinephrine was mediated by beta₁ or beta₂ adrenergic stimulation. We further postulate that the decreased coronary flow and increased stenotic resistance were caused by a passive decrease in radius at the stenotic site.     

Moderate sodium restriction and diuretics in the treatment of hypertension

Using a cross-over type setup with 4 periods of 1 month each in 22 patients with mild, mostly essential hypertension, the antihypertensive action of the following therapeutic regimens were compared: (1) a regular diet and placebo (period RP), (2) a regular diet and 100 mg. hydrochlorothiazide and 100 mg. spironolactone (period RD), (3) a moderate sodium restriction and placebo (LP period), and (4) this diet together with the same diuretics (period LD). The diuretics or placebo were administered on a double blind basis, while the sodium restriction or regular sodium diet was prescribed in an open, but randomized system. The 24 hour urinary sodium averaged 191.1 ± 61.2 mEq. during the RP period and 92.8 ± 41.8 mEq. during the LP period.Compared to the RP period, the reduction in home blood pressures was more important with diuretics alone ($\text{16.1}\text{8.1}$ mm. Hg) than with this moderate sodium restriction alone ($\text{7.7}\text{4.4}$ mm. Hg), while the combination of both produced a statistically significantly (p < 0.005) higher blood pressure reduction ($\text{20.7}\text{10.8}$ mm. Hg).Not only the diuretics but also the sodium restriction increased the serum uric acid, and this could be related to the decreased urinary uric acid clearance.A significant (p < 0.001) correlation (r = 0.66) was obtained between the decrease in systolic blood pressure (expressed in mm. Hg) produced by the sodium restriction (y) and the decrease in 24 hour urinary sodium excretion (expressed in mEq.) produced by the same diet:

$\text{y=?6.58+0.163}\text{x}$

These data suggest that a reduction of the daily NaCl intake from 10 to 5 Gm. could produce a decrease of blood pressure of about $\text{10}\text{5}$ mm. Hg.     

Total and regional myocardial blood flow in aortic regurgitation.

Total, phasic, and regional flow were studied in 12 open-chest dogs with aortic regurgitation. An adjustable catheter device was used to produce aortic regurgitation. Four differently labeled 7 to 9μ microspheres were injected into the left atrium during control, mild (5 to 25 per cent), moderate (25 to 50 per cent), and severe (50 to 80 per cent) regurgitation. Aortic regurgitation (AR) and the ratio of diastolic coronary blood flow to systolic coronary blood flow ($\text{DIAS}\text{SYS}$ RATIO) were measured from the electromagnetic flow tracings. The simultaneous left ventricular and aortic pressures were used to calculate $\text{DPTI}\text{SPTI}$ (diastolic pressure time index to systolic time index). Myocardial flow, flow to major subgroups, and endocardial/epicardial ratios were determined from radioisotope analysis of the left ventricle.Mean absolute control values and mean changes of key variables from control were:

3.

	Control	Mild AR	Mod AR	Severe AR
Heart rate (beats/min.)	163.42	?5.00	?4.831	?8.56
$\text{DPTI}\text{SPTI}$	1.18	?0.121	?0.241	?0.561
Dias/Sys ratio	4.23	?0.28	?1.641	?3.311
Myo. flow (ml./100g./min.)	99.90	?5.63	11.18	21.63
Endocardium (ml./100 g./min.)	97.27	?5.28	10.26	7.39
Epicardium (ml./100 g./min.)	100.15	?7.38	7.88	21.58
$\text{ENDO}\text{EPI}$ ratio	0.99	0.01	0.01	?0.11

1

Denotes significant change from control state (P = 0.05).

The phasic coronary blood flow results in this study are similar to those reported in chronic, intact anesthetized dogs; when the degree of aortic regurgitation increased, there was a significant decrease in diastolic coronary blood flow with an increase in systolic coronary blood flow. Not previously reported are the changes in the distribution of myocardial perfusion. Total myocardial flow increased slightly. There were minimal changes in blood flow to the endocardium which resulted in a slight decrease in the $\text{ENDO}\text{EPI}$ ratio and a decrease in the per cent of flow to the endocardium. These results indicate that, although acute aortic regurgitation produces significant changes in phasic coronary flow, there are much smaller effects on total and regional myocardial blood flow.     

Effect of coronary vasodilation on ventricular fibrillation threshold: Role of exogenous vasodilators and perfusion conditions

Even without myocardial ischemia, coronary blood flow (CBF) constitutes a major determinant of ventricular fibrillation threshold (VFT). To clarify whether abnormal distribution of normal or increased CBF plays any additional role, 14 open-chest chloralose-anesthetized dogs with fixednormalized heart rate, cardiac output, and systemic arterial pressure and separate servocontrolled left main coronary artery perfusion were studied as follows: VFT was determined first with coronary perfusion pressure (CPP) set at systemic level (80 mm Hg). Then CBF index was fixed at control levels (134.0 ± 9.5 ml/min · 100 gm^?1 LV) and coronary vasodilation was induced by intracoronary infusion of adenosine until CPP decreased to 49.0 ± 2.0 mm Hg. Myocardial O₂ consumption, LV pressure, LV $\text{dp}\text{dt}$, and surface ECG remained unchanged. However, VFT decreased in all trials by about 45% (p < 0.001). When CPP was reset to 80 mm Hg while maintaining vasodilation, CBF index increased by 90% to 255.4 ± 15.4 ml/min · 100 gm^?1 LV and VFT by 26% (p < 0.005) from control. Yet these VFT increases in response to intraluminal pharmacologic vasodilation were about 19% (p < 0.002) lower than expected for similar CBF index increases occurring physiologically. We conclude that intraluminal coronary vasodilation not matched by appropriate CBF increase results in substantial decrease of VFT. Moreover, at comparable increase of CBF, spontaneous physiologic vasodilation is more effective than intraluminal pharmacologic coronary vasodilation in increasing VFT.     

Transmural variation in autoregulation of right ventricular blood flow

We examined transmurally the right coronary autoregulatory flow response to varied perfusion pressures in 11 anesthetized, open-chest dogs. Right coronary artery flow was measured electromagnetically, and its transmural distribution was defined with 15-micron radioactive microspheres. Heart rate, mean aortic blood pressure, right ventricular systolic pressure, end-diastolic pressure, and dP/dtmax were constant. At 100 mm Hg, subepicardial flow averaged 0.48 +/- 0.04 ml/min/g, and subendocardial flow averaged 0.56 +/- 0.05 ml/min/g. In contrast to the left coronary circulation, right coronary hypotension did not cause preferential subendocardial ischemia. As right coronary perfusion pressure was decreased from 100 to 40 mm Hg in five dogs, subepicardial and subendocardial flows were reduced similarly by 35-36%. As right coronary perfusion pressure was elevated from 100 to 150 mm Hg in six dogs, right ventricular subepicardial blood flow increased by 31%, whereas subendocardial blood flow increased by 70%. Right ventricular subendocardial-to-subepicardial flow ratios averaged 1.15-1.20 for perfusion pressures of 40 to 120 mm Hg, and they increased to 1.36 +/- 0.05 at 150 mm Hg. Right coronary artery autoregulatory closed-loop gain averaged 0.47 +/- 0.06 between 70 and 100 mm Hg and was greater than zero from 40 to 120 mm Hg. Between 120 and 150 mm Hg, gain fell to -0.15 +/- 0.10. Regional gain varied from 0.59 +/- 0.10 to 0.44 +/- 0.08 in subepicardium as pressure was decreased from 100 to 40 mm Hg. Subendocardial gains were similar to subepicardial gains over this pressure range.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in left ventricular wall dimensions during regional myocardial ischemia

The relation between changes in left ventricular wall systolic thickening and other measures of left ventricular function were studied during regional ischemia in 14 open chest pigs. A fixed decrease in coronary peak blood flow from 46 ± 5 (standard error) to 13 ± 2 ml/min was produced using a screw clamp and flow probe placed around the left anterior descending coronary artery. Myocardial wall thickness was measured with a calibrated harpoon mercury strain gauge placed through the apical portion of the left ventricle and recorded continuously with left ventricular systolic pressure, the first derivative of left ventricular pressure rise ($\text{dP}\text{dt}$) and pressure-derived peak velocity of contraction. During systole, the left ventricle thickened by 10.7 ± 2.1 percent of its total average thickness of 12.7 ± 0.7 mm. Within 6 seconds of the onset of ischemia total myocardial wall thickness decreased from 1.356 ± 0.135 to 0.592 ± 0.081 mm (P < 0.001) or to 45.2 ± 5.1 percent of the control value. During ischemia, changes were noted in both the isovolumic and the ejection phases of systole in addition to left ventricular wall thinning of 0.282 ± 0.02 mm at enddiastole. There was no significant change in left ventricular pressure or its derived values. In two experiments isolated wall thickness alternans was observed. These studies indicate that myocardial wall thickness is more sensitive than ventricular pressure as a measure of local changes in myocardial function during regional myocardial ischemia.